Cyclic amine derivatives and their use as drugs

ABSTRACT

A compound represented by the general formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C 1 -C 6  alkyl addition salt thereof, and their medical applications. These compounds inhibit the action of chemokines such as MIP-1α and/or MCP-1 on target cells, and are useful as therapeutic and/or preventative drugs in diseases, such as atherosclerosis, rheumatoid arthritis, and the like where blood monocytes and lymphocytes infiltrate into tissues.

This is a divisional of application Ser. No. 09/554,562 filed May 16, 2000, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel cyclic amine derivatives.

This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a major role in the initiation, progression or maintenance of the disease.

DESCRIPTION OF RELATED ART

Chemokines are a group of inflammatory/immunomodulatory polypeptide factors which have a molecular weight of 6-15 kD and are produced by a variety of cell types, such as macrophages, monocytes, eosinophils, neutrophiles, fibroblasts, vascular endotherial cells, smooth muscle cells, and mast cells, at inflammatory sites. The chemokines can be classified into two major subfamilies, the CXC chemokines (or α-chemokines) and CC chemokines (or β-chemokines), by the common location of the four conserved cysteine residues and by the differences in the chromosomal locations of the genes encoding them. The first two cysteines of CXC chemokines are separated by one amino acid and those of CC chemokines are adjacent. For example IL-8 (abbreviation for interleukin-8) is a CXC chemokine, while the CC chemokines include MIP-1α/β (abbreviation for macrophage inflammatory protein-1α/β), MCP-1 (abbreviation for monocyte chemoattractant protein-1), and RANTES (abbreviation for regulated upon activation, normal T-cell expressed and secreted). There also exist chemokines which do not fall into either chemokine subfamily. They are lymphotactin, which has only two cysteines and defines the C chemokine, and fractalkine that has a chemokine-like domain in the mucin structure in which the first two cysteines are separated by three amino acids and hence defines CX₃C chemokine. These chemokines promote chemotaxis, cell migration, increase the expression of cellular adhesion molecules such as integrins, and cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Vaddi, K., et al., The Chemokine Facts Book, Academic Press, 1997; Chemoattractant Ligand and Their Receptors, Horuk, R., Ed., CRC Press, 1996; Ward, G. W., et al., Biochem. J., 1998, 333, 457; Luster, A. D., New Engl. J. Med., 1998, 338, 436; Baggiolini, M., Nature, 1998, 392, 565; Rollins, B. J., Blood, 1997, 90, 909; Alam, R., J. Allergy Clin. Immunol., 1997, 99, 273; Hancock, W. W., Am. J. Pathol., 1996, 148, 681; Taub, D. D., Cytokine & Growth Factor Rev., 1996, 7, 335; Strieter, R. M., et al., J. Immunol., 1996, 156, 3583; Furie, M. B., et al., Am. J. Pathol., 1995, 146, 1287; Schall, T. J., et al., Current Opinion in Immunology, 1994, 6, 865; Edginton, S. M., Biotechnology, 1993, 11, 676).

For example, MIP-1α causes a transient increase in intracellular calcium ion concentration levels and induces migration of T lymphocytes, B lymphocytes (see for example, Taub, D. D., et al., Science, 1993, 260, 355; Schall, T. J., et al., J. Exp. Med., 1993, 177, 1821), and eosinophiles (see for example, Rot, A., et al., J. Exp. Med., 1992, 176, 1489), chemotaxis of natural killer cells (see for example, Maghazachi, A. A., et al., J. Immunol., 1994, 153, 4969), expression of integrins (see for example, Vaddi, K., et al., J. Immunol., 1994, 153, 4721), and osteoclast differentiation (see for example, Kukita, T., et al., Lab. Invest., 1997, 76, 399). MIP-1α also enhances IgE and IgG4 production in B cells (see for example, Kimata, H., et al., J. Exp. Med., 1996, 183, 2397) and inhibits hematopoietic stem cell proliferation (see for example, Mayani, H., et al., Exp. Hematol., 1995, 23, 422; Keller, J. R., et al., Blood, 1994, 84, 2175; Eaves, C. J., et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 12015; Bodine, D. M., et al., Blood, 1991, 78, 914; Broxmeyer, H. E., et al., Blood, 1990, 76, 1110).

With respect to the activity of MIP-1α in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G., et al., Science, 1989, 243, 1066); that MIP-1α injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R., et al., J. Immunol., 1994, 152, 1298); that MIP-1α neutralizing antibody has an inhibitory effect or a therapeutic effect in animal models of granuloma (see for example Lukacs, N. W., et al., J. Exp. Med., 1993, 177, 1551), asthma (see for example Lukacs, N. W., et al., Eur. J. Immunol., 1995, 25, 245; Lukacs, N. W., et al., J. Immunol., 1997, 158, 4398), multiple sclerosis (see for example Karpus, W. J., et al., J. Immunol., 1995, 155, 5003; Karpus, W. J., et al., J. Leukoc. Biol., 1997, 62, 681), idiopathic pulmonary fibrosis (see for example Smith, R. E., et al., J. Immunol., 1994, 153, 4704; Smith, R. E., Biol. Signals, 1996, 5, 223), acute lung injury (see for example Shanley, T. P., et al., J. Immunol., 1995, 154, 4793; Standiford, T. J., et al., J. Immunol., 1995, 155, 1515), and rheumatoid arthritis (see for example Kasama, T., et al., J. Clin. Invest., 1995, 95, 2868); that coxsackie virus induced myocarditis and herpes stromal keratitis are inhibited in mice with a disrupted MIP-1α gene (see for example Cook, D. N. et al., Science, 1995, 269, 1583; Tumpey, T. M., et al., J. Virology, 1998, 72, 3705); and that significant expression of MIP-1α is observed in patients with chronic inflammatory diseases of lung (see for example Standiford, T. J., et al., J. Immunol., 1993, 151, 2852), hypersensitivity pneumonitis (see for example Denis, M., Am. J. Respir. Crit. Care Med., 1995, 151, 164), rheumatoid arthritis (see for example Koch, A. E., et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (see for example Lahrtz, F., et al., J. Neuroimmunol.; 1998, 85, 33), and chronic inflammation of muscle (see for example Adams, E. M., et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). These studies indicate that MIP-1α is deeply involved in the local attraction of various subtypes of leukocytes and the initiation, progression and maintenance of resulting inflammatory response.

MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes (see for example Valente, A. J., et al., Biochemistry, 1988, 27, 4162; Matsushima, K., et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, B. J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B. J., et al., Blood, 1991, 78, 1112; Jiang, Y., et al., J. Immunol., 1992, 148, 2423; Vaddi, K., et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes (see for example Carr, M. W., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see for example Loetscher, P., et al., FASEB J., 1994, 8, 1055) and natural killer cells (see for example Loetscher, P., etal., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol., 1994, 24, 3233), as well as mediating histamine release by basophils (see for example Alam, R., et al., J. Clin. Invest., 1992, 89, 723; Bischoff, S. C., et al., J. Exp. Med., 1992, 175, 1271; Kuna, P., et al., J. Exp. Med., 1992, 175, 489).

In addition, high expression of MCP-1 has been reported in diseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation or progression of diseases, such as atherosclerosis (see for example Hayes, I. M., et al., Arterioscler. Thromb. Vasc. Biol., 1998, 18, 397; Takeya, M. et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S., et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; Nelken, N. A., J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see for example Koch, A. E., etal., J. Clin. Invest., 1992, 90, 772; Akahoshi, T., et al., Arthritis Rheum., 1993, 36, 762; Robinson, E., et al., Clin. Exp. Immunol., 101, 398), nephritis (see for example Noris, M., et al., Lab. Invest., 1995, 73, 804; Wada, T., at al., Kidney Int., 1996, 49, 761; Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (see for example Saitoh, A., et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H., et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis, pulmonary sarcoidosis (see for example Sugiyama, Y., et al., Internal Medicine, 1997, 36, 856), asthma (see for example Karina, M., et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; Sousa, A. R., et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see for example McManus, C., et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see for example Gillitzer, R., et al., J. Invest. Dermatol., 1993, 101, 127), inflammatory bowel disease (see for example Grimm, M. C., et al., J. Leukoc. Biol., 1996, 59, 804; Reinecker, H. C., et al., Gastroenterology, 1995, 106, 40), myocarditis (see for example Seino, Y., et al., Cytokine, 1995, 7, 301), endometriosis (see for example Jolicoeur, C., et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see for example Zeyneloglu, H. B., et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see for example Aurust, P., et al., Circulation, 1998, 97, 1136), chronic liver disease (see for example Marra, F., et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (see for example Lahrtz, F., et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see for example Wong, M.; et al., J. Rheumatol., 1997, 24, 1179) and sepsis (see for example Salkowski, C. A.; et al., Infect. Immun., 1998, 66, 3569). Furthermore, anti-MCP-1 antibody has been reported to show an inhibitory effect or a therapeutic effect in animal models of rheumatoid arthritis (see for example Schimmer, R. C., et al., J. Immunol., 1998, 160, 1466; Schrier, D. J., J. Leukoc. Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see for example Karpus, W. J., et al., J. Leukoc. Biol., 1997, 62, 681), nephritis (see for example Lloyd, C. M., et al., J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB J., 1996, 10, 1418), Asthma (see for example Gonzalo, J. -A., et al., J. Exp. Med., 1998, 188, 157; Lukacs, N. W., J. Immunol., 1997, 158, 4398), atherosclerosis (see for example Guzman, L. A., et al., irculation, 1993, 88 (suppl.), I-371), delayed type hypersensitivity (see for example Rand, M. L., et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (see for example Kimura, H., et al., Lab. Invest., 1998, 78, 571), and intraperitoneal adhesion (see for example Zeyneloglu, H. B., et al., Am. J. Obstet. Gynecol., 1998, 179, 438). A peptide antagonist of MCP-1, MCP-1(9-76), has been also reported to inhibit arthritis in the mouse model (see Gong, J. -H., J. Exp. Med., 1997, 186, 131), as well as studies in MCP-1-deficient mice have shown that MCP-1 is essential for monocyte recruitment in vivo (see Lu, B., et al., J. Exp. Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).

These data indicate that chemokines such as MIP-1α and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis (see for example Rovin, B. H., et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C., et al., Curr. Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P., et al., Allergy and Asthma Proc., 1998, 19, 121; Ransohoff, R. M., et al., Trends Neurosci., 1998, 21, 154; MacDermott, R. P., et al., Inflammatory Bowel Diseases, 1998, 4, 54). Therefore, drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in the diseases.

Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations. So far, at least five CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokine receptors (CCR1-CCR8) have been identified. For example IL-8 is a ligand for CXCR1 and CXCR2, MIP-1α is that for CCR1 and CCR5, and MCP-1 is that for CCR2 A and CCR2 B (for reference, see for example, Holmes, W. E., et al., Science 1991, 253, 1278-1280; Murphy P. M., et al., Science, 253, 1280-1283; Neote, K. etal., Cell, 1993, 72, 415-425; Charo, I. F., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C. A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, P. M., Annual Review of Immunology, 1994, 12, 592-633). It has been reported that lung inflammation and granuroma formation are suppressed in CCR1-deficient mice (see Gao, J. -L., et al., J. Exp. Med., 1997, 185, 1959; Gerard, C., et al., J. Clin. Invest., 1997, 100, 2022), and that recruitment of macrophages and formation of atherosclerotic lesion decreased in CCR2-deficient mice (see Boring, L., et al., Nature, 1998, 394, 894; Kuziel, W. A., et al., Proc. Natl. Acad. Sci., USA, 1997, 94, 12053; Kurihara, T., et al., J. Exp. Med., 1997, 186, 1757; Boring, L., et al., J. Clin. Invest., 1997, 100, 2552). Therefore, compound which inhibit the binding of chemokines such as MIP-1α and/or MCP-1 to these receptors, that is, chemokine receptor antagonist, may be useful as drugs which inhibit the action of chemokines such as MIP-1α and/or MCP-1 on the target cells, but there are no drugs known to have such effects.

The cyclic amine derivatives provided by the present invention is quite novel. Recently, it has been reported that the diphenylmethane derivatives (WO9724325; Hesselgesser, J., et al., J. Biol. Chem., 1998, 273, 15687), piperidine derivatives (JP9-249566), imidazobenzodiazepine derivatives (JP9-249570), benzazocine derivatives (JP9-255572), tricyclic compounds with cyclic amino group (WO9804554), phenothiazine derivatives (Bright, C., et al., Bioorg. Med. Chem. Lett., 1998, 8, 771), pieprazine derivatives (WO9744329), benzimidazole derivatives (WO9806703), distamycin analogues (Howard, O. M. Z., et al., J. Med. Chem., 1998, 41, 2184), bis-acridine derivatives (WO9830218), spiro-substituted azacycles (WO9825604; WO9825605), substituted aryl piperazines (WO9825617), aminoquinoline derivatives (WO9827815), 3-arylpiperidine derivatives (WO9831364), hexanoic amide derivatives (WO9838167), and other small molecules (WO9744329; WO9802151; WO9804554) have antagonistic activity of chemokine receptor, such as CXCR1, CXCR4, CCR1, CCR2, CCR3, and CCR5. However, these compounds differ from the compound of the present invention.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide small molecule compound which inhibits the binding of chemokines such as MIP-1α and/or MCP-1 to their receptors on the target cells.

It is another object of the present invention to establish a method to inhibit the binding to the receptors on the target cells and/or effects on target cells of chemokines such as MIP-1α and/or MCP-1.

It is an additional object of the present invention to propose a method for the treatment of diseases for which the binding of chemokines such as MIP-1α and/or MCP-1 to the receptor on the target cell is one of the causes.

As a result of intensive studies, the present inventors discovered that a cyclic amine derivative having a arylalkyl group, its pharmaceutically acceptable C₁-C₆ alkyl addition salt or its pharmaceutically acceptable acid addition salt has an excellent activity to inhibit the binding of chemokines such as MIP-1α and/or MCP-1 and the like to the receptor of a target cell, which has led to the completion of this invention.

That is, the present invention is a compound of the formula (I) below:

a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt thereof (Invention 1),

wherein R¹ is a phenyl group, a C₃-C₈ cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C₁-C₆ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₃-C₅ alkylene group, a C₂-C₄ alkylenoxy group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₄-C₈ N-cycloalkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a C₃-C₈ (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, a divalent group represented by the formula: —NH(C═O)O—, a divalent group represented by the formula: —NH(C═S)O—, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group;

R² is a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C₁-C₆ alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group, and when j=0, R² is not a hydroxy group;

j represents an integer of 0-2;

k represents an integer of 0-2;

m represents an integer of 2-4;

n represents 0 or 1;

R³ is a hydrogen atom or a C₁-C₆ alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group;

R⁴ and R⁵ are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C₁-C₆ alkyl group, in which the C₁-C₆ alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, amercapto group, a guanidino group, a C₃-C₈ cycloalkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R⁴ and R⁵ taken together form a 3 to 6 membered cyclic hydrocarbon;

p represents 0 or 1;

q represents 0 or 1;

G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, —CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O—, or —O—CO—NH—, wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group, or R⁷ taken together with R⁵ represents C₂-C₆ alkylene group;

R⁶ is a phenyl group, a C₃-C₈ cycloalkyl group, a C₃-C₈ cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₃-C₆ cyclbalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₃-C₈ cycloalkyloxy group, a C₁-C₆ alkylthio group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C₁-C₆ alkyl)sulfamoyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, a benzylamino group, a C₂-C₇ (alkoxycarbonyl)amino group, a C₁-C₆ (alkylsulfonyl)amino group, or a bis(C₁-C₆ alkylsulfonyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group.

Also the present invention is a method of inhibiting the binding of a chemokine to the receptor. of a target cell and/or its action on a target cell using a pharmaceutical preparation containing a therapeutically effective amount of a compound represented by the above formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C₁-C₆ alkyl addition salt thereof (Invention 2).

Here, the compound represented by the above formula (I) have activities to inhibit the binding of chemokines such as MIP-1α and/or MCP-1 and the like to the receptor of a target cell and activities to inhibit physiological activities of cells caused by chemokines such as MIP-1α and/or MCP-1 and the like.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) On Invention 1

In the above formula (I), R¹ is a phenyl group, a C₃-C₈ cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C₁-C₆ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₃-C₅ alkylene group, a C₂-C₄ alkylenoxy group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₄-C₈ N-cycloalkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a C₃-C₈ (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, a divalent group represented by the formula: —NH(C═O)O—, a divalent group represented by the formula: —NH(C═S)O—, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group.

The “C₃-C₈ cycloalkyl group” for R¹ means a cyclic alkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl group, specifically including a cyclopropyl, cyclopentyl, and cyclohexyl group.

The “aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof” for R¹ is specifically, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (furazanyl), thiadiazolyl group and the like, preferably including a thienyl, furyl, pyrrolyl, isoxazolyl, and pyridyl group.

The “condensed ring” for R¹ means a ring obtained by the condensation with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom of a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and/or a nitrogen atom, at any possible sites, suitably and specifically for example, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl (benzofurazanyl), and benzothiadiazolyl group.

Among them, a phenyl group and an isoxazolyl group can be listed as a preferred specific example for R¹.

The “halogen atom” as a substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹ includes a fluorine atom, chlorine atom, bromine atom, and iodine atom, suitably including a fluorine atom, chlorine atom, and bromine atom.

The “C₁-C₆ alkyl group” as a substituent for R¹ means a C₁-C₆ straight-chain or a branched alkyl group such as a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl, 1-ethylbutyl group, and the like, suitably specifically including a methyl, ethyl, propyl, and isopropyl group.

The “C₂-C₈ cycloalkyl group” as a substituent for R¹ is the same as defined for the aforementioned “C₃-C₈ cycloalkyl group” for R¹, where the same examples can be given for the preferred specific examples.

The “C₂-C₆ alkenyl group” as a substituent for R¹ means a C₂-C₆ straight-chain or a branched alkenyl group such as a vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 4-pentenyl, 5-hexenyl, 4-methyl-3-pentenyl group, and the like, suitably specifically including a vinyl and 2-methyl-1-propenyl group.

The “C₁-C₆ alkoxy group” as a substituent for R¹ means group consisting of the aforementioned C₁-C₆ alkyl group and oxy group, specifically, for example, a methoxy and ethoxy group.

The “C₁-C₆ alkylthio group” as a substituent for R¹ means group consisting of the aforementioned C₁-C₆ alkyl group and thio group, specifically, for example, a methylthio and ethylthio group.

The “C₃-C₈ alkylene group” as a substituent for R¹ means the C₃-C₈ divalent alkylene group such as a trimethylene, tetramethylene, pentamethylene, and 1-methyltrimethylene group, specifically, for example, a trimethylene and a tetramethylene group.

The “C₂-C₄ alkylenoxy group” as a substituent for R¹ means group consisting of the aforementioned C₂-C₄ divalent alkylene group and oxy group such as a ethylenoxy (—CH₂CH₂O—), trimethylenoxy (—CH₂CH₂CH₂O—), tetramethylenoxy (—CH₂CH₂CH₂CH₂O—), and 1,1-dimethylethylenoxy (—CH₂C(CH₃)₂O—) group, specifically, for example, a ethylenoxy and trimethylenoxy group.

The “C₁-C₆ alkylenedioxy group” as a substituent for R¹ means group consisting of C₁-C₆ divalent alkylene group and two oxy groups such as a methylenedioxy (—OCH₂O—), ethylenedioxy (—OCH₂CH₂O—), trimethylenedioxy (—OCH₂CH₂CH₂O—, and propylenedioxy (—OCH₂CH(CH₃)O—) group, specifically, for example, a methylenedioxy and ethylenedioxy group.

The “C₂-C₇ alkanoyl group” as a substituent for R¹ means C₂-C₇ straight-chain or branched alkanoyl group such as an acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl, 3,3-dimethylbutanoyl, 5-methylhexanoyl group, and the like, where the preferred and specific example includes an acetyl group.

The “C₂-C₇ alkoxycarbonyl group” as a substituent for R¹ means group consisting of the aforementioned C₁-C₆ alkoxy group and carbonyl group, preferably and specifically for example, a methoxycarbonyl and ethoxycarbonyl group.

The “C₂-C₇ alkanoyloxy group” as a substituent for R¹ means group consisting of the aforementioned C₂-C₇ alkanoyl group and oxy group, specifically, for example, an acetyloxy group.

The “C₂-C₇ alkanoylamino group” as a substituent for R¹ means group consisting of the aforementioned C₂-C₇ alkanoyl group and amino group, specifically, for example, an acetylamino group.

The “C₂-C₇ N-alkylcarbamoyl group” as a substituent for R¹ means group consisting of the aforementioned C₁-C₄ alkyl group and carbamoyl group, specifically, for example, a N-methylcarbamoyl and N-ethylcarbamoyl group.

The “C₄-C₇ N-cycloalkylcarbamoyl group” as a substituent for R¹ means group consisting of the aforementioned C₃-C₈ cycloalkyl group and carbamoyl group, specifically, for example, a N-cyclopentylcarbamoyl and N-cyclohexylcarbamoyl group.

The “C₁-C₆ alkylsulfonyl group” as a substituent for R¹ means group consisting of the aforementioned C₁-C₆ alkyl group and sulfonyl group, preferably and specifically, for example, a methylsulfonyl group.

The “C₃-C₈ (alkoxycarbonyl)methyl group” as a substituent for R¹ means group consisting of the aforementioned C₂-C₇ alkoxycarbonyl group andmethyl group, preferably and specifically for example, a (methoxycarbonyl)methyl and (ethoxycarbonyl)methyl group.

The “mono(C₁-C₆ alkyl)amino group” as a substituent for R¹ means amino group substituted with one of the aforementioned C₁-C₆ alkyl group, preferably and specifically, for example, a methylamino and ethyl amino group.

The “di(C₁-C₆ alkyl) amino group” as a substituent for R¹ means amino group substituted with the same or different two C₁-C₆ alkyl group aforementioned, preferably and specifically, for example, a dimethylamino; diethylamino, and N-ethyl-N-methylamino group.

Among them, a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₂-C₄ alkylenoxy group, a methylenedioxy group, a N-phenylcarbamoyl group, an amino group, a mono (C₁-C₆ alkyl)amino group, and a di(C₁-C₆ alkyl)amino group can be listed as a preferred specific example for substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹.

Furthermore above substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹ are optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group. The halogen atom, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group are the same as defined for the aforementioned substituents for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

In the above formula (I), R² represents a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C₁-C₆ alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group, and when j=0, R² is not a hydroxy group.

The C₁-C₆ alkyl group and C₂-C₇ alkoxycarbonyl group for R² are the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The halogen atom, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group as substituents for the C₁-C₆ alkyl or phenyl group in R² are the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

Among them, a hydrogen atom is a preferred specific example for R².

In the above formula (I), j represents an integer of 0-2. It is particularly preferred for j to be 0.

In the above formula (I), k represents an integer of 0-2 and m represents an integer of 2-4. It is preferred to use a 2-substituted pyrrolidine in which k is 0 and m is 3, a 3-substituted pyrrolidine in which k is 1 and m is 2, a 3-substituted piperidine in which k is 1 and m is 3, a 4-substituted piperidine in which k is 2 and m is 2, or 3-substituted hexahydroazepine in which k is 1 and m is 4.

n in the above formula (I) represents 0 or 1.

Especially, 3-amidopyrrolidines in which k is 1, m is 2, and n is 0 and 4-(amidomethyl)piperidines in which k is 2, m is 2, and n is 1 can be listed as a particularly preferred example.

R³ in the above formula (I) represents a hydrogen atom or a C₁-C₆ alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group.

The C₁-C₆ alkyl group for R¹ is the same as defined for the aforementioned substituents for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, specifically, for example, a methyl, ethyl and propyl group.

The halogen atom, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group as substituents for the phenyl group, which is a substituent for C₁-C₆ alkyl group in R¹, are the same as defined for the aforementioned substituents for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

Among them, a hydrogen atom is a preferred specific example for R³.

In the above formula (I), R⁴ and R⁵ are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C₁-C₆ alkyl group, in which the C₁-C₆ alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C₃-C₈ cycloalkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R⁴ and R⁵ taken together form a 3 to 6 membered cyclic hydrocarbon.

The C₁-C₆ alkyl group for R⁴ and R⁵ is the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The halogen atom, C₁-C₆ alkoxy group, C₁-C₆ alkylthio group, C₂-C₇ alkanoyl group, C₂-C₇ alkoxycarbonyl group, C₂-C₇ alkanoyloxy group, C₂-C₇ alkanoylamino group, C₂-C₇ N-alkylcarbamoyl group, C₁-C₆ alkylsulfonyl group, mono(C₁-C₆ alkyl)amino group, and di(C₁-C₆ alkyl)amino group as a substituent for the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The C₃-C₈ cycloalkyl group and aromatic heterocyclic group having 1-3heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof as substituent for the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the aforementioned group for R¹, and the same examples can be listed as preferred specific examples.

The halogen atom, C₁-C₆ alkyl group, and C₁-C₆ alkoxy group for the substituent for the phenyl group which is substituent for the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The “3 to 6 membered cyclic hydrocarbon” consisting of R⁴, R⁵, and the adjacent carbon atom includes a cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

Among them, a hydrogen atom and a C₁-C₆ alkyl group can be listed as a preferred specific example for R⁴ and R⁵.

In the above formula (I), p represents 0 or 1, and q represents 0 or 1. It is particularly preferred for both p and q to be 0.

In the above formula (I), G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, —CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O—, or —O—CO—NH—, wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group, or R⁷ taken together with R⁵ represents a C₂-C₆ alkylene group.

In the above formula, —CO— means a carbonyl group, —SO₃— means a sulfonyl group, and —CS— means a thiocarbonyl group. Preferred G group is specifically, for example, those represented by the formula —NR⁷—CO— and —NH—CO—NH—.

The C₁-C₆ alkyl group for R⁷ are the same as defined for the aforementioned substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The “C₂-C₆ alkylene group” consisting of R⁵ and R⁷ means C₂-C₆ straight-chain or branched alkylene group such as a methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, pentamethylene group, and the like, suitably and specifically including a ethylene, trimethylene and tetramethylene group.

A hydrogen atom is a preferred specific example for R⁷.

In the above formula (I), R⁶ is a phenyl group, a C₃-C₈ cycloalkyl group, a C₃-C₈ cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₃-C₈ cycloalkyloxy group, a C₁-C₆ alkylthio group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C₁-C₆ alkyl)sulfamoyl group, an amino group, a mono(C₁-C₆ alkyl) amino group, a di(C₁-C₆ alkyl)amino group, a benzylamino group, a C₂-C₇ (alkoxycarbonyl)amino group, a C₁-C₆ (alkylsulfonyl)amino group, or a bis(C₁-C₆ alkylsulfonyl)amino group.

The C₃-C₈ cycloalkyl group, aromatic heterocyclic group having 1-3heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, and the condensed ring for R⁶ are the same as defined for the aforementioned R1, and the same examples can be listed as preferred specific examples.

The “C₃-C₈ cycloalkenyl group” for R⁶ means a cyclic alkenyl group such as a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl group, specifically including a 1-cyclopentenyl and 1-cyclohexenyl group.

Among them, a phenyl group, a furyl group, and a thienyl group can be listed as a preferred specific example for R⁶.

The halogen atom, C₁-C₆ alkyl group, C₂-C₆alkenyl group, C₁-C₆ alkoxy group, C₁-C₆ alkylthio group, C₁-C₆ alkylenedioxy group, C₂-C₇ alkanoyl group, C₂-C₇ alkoxycarbonyl group, C₂-C₇ alkanoyloxy group, C₂-C₇ alkanoylamino group, C₂-C₇ N-alkylcarbamoyl group, C₁-C₆ alkylsulfonyl group, mono(C₁-C₆ alkylamino group, and di (C₁-C₆ alkyl) amino group as a substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁴ are the same as defined for the aforementioned substituent for the phenyl group, C₁-C₂ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

The C₃-C₈ cycloalkyl group as a substituent for R⁶ is the same as defined for the aforementioned C₃-C₈ cycloalkyl group for R¹, where the same examples can be given for the preferred specific examples.

The “C₃-C₈ cycloalkyloxy group” as a substituent for R⁶ means group consisting of the aforementioned C₃-C₈ cycloalkyl group and oxy group, specifically, for example, a cyclopropyloxy, cyclopentyloxy, and cyclohexyloxy group.

The “N,N-di(C₁-C₆ alkyl)sulfamoyl group” as a substituent for R⁶ means sulfamoyl group substituted with the same or different two C₁-C₆ alkyl group aforementioned, preferably and specifically, for example, a N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-ethyl-N-methylsulfamoyl group.

The “C₂-C₇ (alkoxycarbonyl)amino group” as a substituent for R⁶ means group consisting of the aforementioned C₂-C₇ alkoxycarbonyl group and amino group, specifically, for example, a (methoxycarbonyl)amino and (ethoxycarbonyl)amino group.

The “C₁-C₆ (alkylsulfonyl)amino” group as a substituent for R⁶ means group consisting of the aforementioned C₁-C₆ alkylsulfonyl group and amino group, specifically, for example, a (methylsulfonyl)amino group.

The “bis(C₁-C₆ alkylsulfonyl)amino” group as a substituent for R⁶ means amino group substituted with the same or different two C₁-C₆ alkylsulfonyl group aforementioned, preferably and specifically, for example, a bis(methylsulfonyl)amino group.

Among them, a halogen atom, a mercapto group, a nitro group, a thiocyanato group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a phenyl group, a phenylsulfonyl group, a C₂-C₇ alkanoylamino group or an amino group can be listed as preferred specific example for substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁶.

Furthermore above substituents for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁶ are optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group.

The halogen atom, C₁-C₆ alkyl group, C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, mono(C₁-C₆ alkyl)amino group, and di(C₁-C₆ alkyl)amino group are the same as defined for the aforementioned substituents for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹, and the same examples can be listed as preferred specific examples.

(2) On Invention 2

The compound represented by the formula (I) above, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt can be used to prepare a chemokine receptor antagonist preparation of the present invention by formulating the therapeutically effected amount and a carrier and/or diluent into a pharmaceutical composition. Thus, the cyclic amine derivatives shown by the above formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt can be administered orally or by parenterally, for example, intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.

The oral administration can be accomplished in the form of tablets, pills, granules, powder, solution, suspension, capsules, etc.

The tablets for example can be prepared using a vehicle such as lactose, starch and crystallized cellulose; binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc.

Pills, powder and granule preparations can be prepared by a standard method using the vehicles mentioned above. Solution or suspension can be prepared by a standard method using glycerin ester such as tricaprylin and triacetinoralcoholssuchasethanol. Capsules can be made by charging granules, powder or solution in gelatin, etc.

Subcutaneous, intramuscular or intravenous preparations can be prepared as an injection using aqueous or nonaqueous solution. Aqueous solution for example may include isotonic sodium chloride solution. Nonaqueous solutions may include for example, propyleneglycol, polyethyleneglycol, olive oil, ethyl oleate, etc., and optionally, one can add antiseptics and stabilizers. For injection, one can be sterilized by filtration through a bacterial filter or combination of disinfectant.

Percutaneous administration may be in the form of an ointment or cream, and ointment can be prepared in the standard manner using fatty oils such as castor oil and olive oil, or Vaseline, while creams can be made using fatty oils or emulsifying agent such as diethyleneglycol and sorbitan esters of fatty acid.

For intrarectal administration, one can use standard suppositories using gelatin soft capsules, etc.

The cyclic amine derivatives of the present invention, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt is administered at a dose that varies depending on the type of disease, route of administration, age and sex of patient, and severity of disease, but is likely to be 1-500 mg/day in an average adult.

(3) Matter common throughout Invention 1 and Invention 2

Preferred specific examples for the cyclic amine compound in the above formula (I) include compound having each substituent as shown in the following Tables 1.1-1.201.

In the Tables 1.1-1.201, “chirality” means configuration of the asymmetric carbon atom on the cyclic amine. “R” shows that the asymmetric carbon atom has a R configuration, “S” shows that the asymmetric carbon atom has a S configuration, and “−” means racemate or that the compound do not have a asymmetric carbon atom on the nitrogen containing ring. [Table 1.1-Table 1.201]

TABLE 1.1 Compd. No.

k m n chirality R³

 1

1 2 0 — H

 2

1 2 0 — H

 3

1 2 0 — H

 4

1 2 0 — H

 5

1 2 0 S H

 6

1 2 0 S H

 7

1 2 0 S H

 8

1 2 0 S H

 9

1 2 0 S H

10

1 2 0 S H

11

1 2 0 S H

TABLE 1.2 Compd. No.

k m n chirality R³

12

1 2 0 S H

13

1 2 0 S H

14

1 2 0 S H

15

1 2 0 S H

16

1 2 0 S H

17

1 2 0 S H

18

1 2 0 S H

19

1 2 0 S H

20

1 2 0 S H

21

1 2 0 S H

22

1 2 0 S H

TABLE 1.3 Compd. No.

k m n chirality R³

23

1 2 0 S H

24

1 2 0 S H

25

1 2 0 S H

26

1 2 0 S H

27

1 2 0 S H

28

1 2 0 S H

29

1 2 0 R H

30

1 2 0 R H

31

1 2 0 R H

32

1 2 0 R H

33

1 2 0 R H

TABLE 1.4 Compd. No.

k m n chirality R³

34

1 2 0 R H

35

1 2 0 R H

36

1 2 0 R H

37

1 2 0 R H

38

1 2 0 R H

39

1 2 0 R H

40

1 2 0 R H

41

1 2 0 R H

42

1 2 0 R H

43

1 2 0 R H

44

1 2 0 R H

TABLE 1.5 Compd. No.

k m n chirality R³

45

1 2 0 R H

46

1 2 0 R H

47

1 2 0 R H

48

1 2 0 R H

49

1 2 0 R H

50

1 2 0 R H

51

1 2 0 R H

52

1 2 0 R H

53

1 2 0 R H

54

1 2 0 R H

55

1 2 0 R H

TABLE 1.6 Compd. No.

k m n chirality R³

56

1 2 0 R H

57

1 2 0 R H

58

1 2 0 R H

59

1 2 0 R H

60

1 2 0 R H

61

1 2 0 R H

62

1 2 0 R H

63

1 2 0 R H

64

1 2 0 R H

65

1 2 0 R H

66

1 2 0 R H

TABLE 1.7 Compd. No.

k m n chirality R³

67

1 2 0 R H

68

1 2 0 R H

69

1 2 0 R H

70

1 2 0 R H

71

1 2 0 R H

72

1 2 0 R H

73

1 2 0 R H

74

1 2 0 R H

75

1 2 0 R H

76

1 2 0 R H

77

1 2 0 R H

TABLE 1.8 Compd. No.

k m n chirality R³

78

1 2 0 R H

79

1 2 0 R H

80

1 2 0 R H

81

1 2 0 R H

82

1 2 0 — —CH₃

83

1 2 0 R H

84

1 2 0 R H

85

1 2 0 — H

86

1 2 0 — H

87

1 2 0 S H

88

1 2 0 S H

TABLE 1.9 Compd. No.

k m n chirality R³

89

1 2 0 S H

90

1 2 0 S H

91

1 2 0 S H

92

1 2 0 S H

93

1 2 0 S H

94

1 2 0 S H

95

1 2 0 S H

96

1 2 0 S H

97

1 2 0 S H

98

1 2 0 S H

99

1 2 0 S H

TABLE 1.10 Compd. No.

k m n chirality R³

100

1 2 0 S H

101

1 2 0 S H

102

1 2 0 S H

103

1 2 0 S H

104

1 2 0 S H

105

1 2 0 S H

106

1 2 0 S H

107

1 2 0 S H

108

1 2 0 S H

109

1 2 0 S H

110

1 2 0 S H

TABLE 1.11 Compd. No.

k m n chirality R³

111

1 2 0 R H

112

1 2 0 R H

113

1 2 0 R H

114

1 2 0 R H

115

1 2 0 R H

116

1 2 0 R H

117

1 2 0 R H

118

1 2 0 R H

119

1 2 0 R H

120

1 2 0 R H

121

1 2 0 R H

TABLE 1.12 Compd. No.

k m n chirality R³

122

1 2 0 R H

123

1 2 0 R H

124

1 2 0 R H

125

1 2 0 R H

126

1 2 0 R H

127

1 2 0 R H

128

1 2 0 R H

129

1 2 0 R H

130

1 2 0 R H

131

1 2 0 R H

132

1 2 0 R H

TABLE 1.13 Compd. No.

k m n chirality R³

133

1 2 0 R H

134

1 2 0 R H

135

1 2 0 R H

136

1 2 0 R H

137

1 2 0 R H

138

1 2 0 R H

139

1 2 0 R H

140

1 2 0 R H

141

1 2 0 R H

142

1 2 0 R H

143

1 2 0 R H

TABLE 1.14 Compd. No.

k m n chirality R³

144

1 2 0 R H

145

1 2 0 R H

146

1 2 0 R H

147

1 2 0 R H

148

1 2 0 R H

149

1 2 0 R H

150

1 2 0 R H

151

1 2 0 R H

152

1 2 0 R H

153

1 2 0 R H

154

1 2 0 R H

TABLE 1.15 Compd. No.

k m n chirality R³

155

1 2 0 R H

156

1 2 0 R H

157

1 2 0 R H

158

1 2 0 R H

159

1 2 0 R H

160

1 2 0 R H

161

1 2 0 R H

162

1 2 0 R H

163

1 2 0 R H

164

1 2 0 R H

165

1 2 0 R H

TABLE 1.16 Compd. No.

k m n chirality R³

166

1 2 0 R H

167

1 2 0 R H

168

1 2 0 R H

169

1 2 0 R H

170

1 2 0 R H

171

1 2 0 R H

172

1 2 0 R H

173

1 2 0 R H

174

1 2 0 R H

175

1 2 0 R H

176

1 2 0 R H

TABLE 1.17 Compd. No.

k m n chirality R³

177

1 2 0 R H

178

1 2 0 R H

179

1 2 0 R H

180

1 2 0 R H

181

1 2 0 R H

182

1 2 0 R H

183

1 2 0 R H

184

1 2 0 R H

185

1 2 0 R H

186

1 2 0 R H

187

1 2 0 R H

TABLE 1.18 Compd. No.

k m n chirality R³

188

1 2 0 R H

189

1 2 0 R H

190

1 2 0 R H

191

1 2 0 R H

192

1 2 0 R H

193

1 2 0 R H

194

1 2 0 R H

195

1 2 0 R H

196

1 2 0 R H

197

1 2 0 R H

198

1 2 0 R H

TABLE 1.19 Compd. No.

k m n chirality R³

199

1 2 0 R H

200

1 2 0 R H

201

1 2 0 R H

202

1 2 0 R H

203

1 2 0 R H

204

1 2 0 R H

205

1 2 0 R H

206

1 2 0 R H

207

1 2 0 R H

208

1 2 0 R H

209

1 2 0 R H

TABLE 1.20 Compd. No.

k m n chirality R³

210

1 2 0 R H

211

1 2 0 R H

212

1 2 0 R H

213

1 2 0 R H

214

1 2 0 — H

215

1 2 0 — H

216

1 2 0 — H

217

1 2 0 — H

218

1 2 0 — H

219

1 2 0 — H

220

1 2 0 — H

TABLE 1.21 Compd. No.

k m n chirality R³

221

1 2 0 — H

222

1 2 0 — H

223

1 2 0 — H

224

1 2 0 — H

225

1 2 0 — H

226

1 2 0 — H

227

1 2 0 — H

228

1 2 0 — H

229

1 2 0 — H

230

1 2 0 — H

231

1 2 0 — H

TABLE 1.22 Compd. No.

k m n chirality R³

232

1 2 0 — H

233

1 2 0 — H

234

1 2 0 — H

235

1 2 0 — H

236

1 2 0 — H

237

1 2 0 — H

238

1 2 0 — H

239

1 2 0 S H

240

1 2 0 S H

241

1 2 0 S H

242

1 2 0 S H

TABLE 1.23 Compd. No.

k m n chirality R³

243

1 2 0 S H

244

1 2 0 S H

245

1 2 0 S H

246

1 2 0 S H

247

1 2 0 S H

248

1 2 0 S H

249

1 2 0 S H

250

1 2 0 S H

251

1 2 0 S H

252

1 2 0 S H

253

1 2 0 S H

TABLE 1.24 Compd. No.

k m n chirality R³

254

1 2 0 S H

255

1 2 0 S H

256

1 2 0 S H

257

1 2 0 S H

258

1 2 0 S H

259

1 2 0 S H

260

1 2 0 S H

261

1 2 0 S H

262

1 2 0 S H

263

1 2 0 S H

264

1 2 0 S H

TABLE 1.25 Compd. No.

k m n chirality R³

265

1 2 0 S H

266

1 2 0 S H

267

1 2 0 S H

268

1 2 0 S H

269

1 2 0 S H

270

1 2 0 S H

271

1 2 0 S H

272

1 2 0 S H

273

1 2 0 S H

274

1 2 0 S H

275

1 2 0 S H

TABLE 1.26 Compd. No.

k m n chirality R³

276

1 2 0 S H

277

1 2 0 S H

278

1 2 0 S H

279

1 2 0 S H

280

1 2 0 S H

281

1 2 0 S H

282

1 2 0 S H

283

1 2 0 S H

284

1 2 0 S H

285

1 2 0 R H

286

1 2 0 R H

TABLE 1.27 Compd. No.

k m n chirality R³

287

1 2 0 R H

288

1 2 0 R H

289

1 2 0 R H

290

1 2 0 R H

291

1 2 0 R H

292

1 2 0 R H

293

1 2 0 R H

294

1 2 0 R H

295

1 2 0 R H

296

1 2 0 R H

297

1 2 0 R H

TABLE 1.28 Compd. No.

k m n chirality R³

298

1 2 0 R H

299

1 2 0 R H

300

1 2 0 R H

301

1 2 0 R H

302

1 2 0 R H

303

1 2 0 R H

304

1 2 0 R H

305

1 2 0 R H

306

1 2 0 R H

307

1 2 0 R H

308

1 2 0 R H

TABLE 1.29 Compd. No.

k m n chirality R³

309

1 2 0 R H

310

1 2 0 R H

311

1 2 0 R H

312

1 2 0 R H

313

1 2 0 R H

314

1 2 0 R H

315

1 2 0 R H

316

1 2 0 R H

317

1 2 0 R H

318

1 2 0 R H

319

1 2 0 R H

TABLE 1.30 Compd. No.

k m n chirality R³

320

1 2 0 R H

321

1 2 0 R H

322

1 2 0 R H

323

1 2 0 R H

324

1 2 0 R H

325

1 2 0 R H

326

1 2 0 R H

327

1 2 0 R H

328

1 2 0 R H

329

1 2 0 R H

330

0 3 1 — H

TABLE 1.31 Compd. No.

k m n chirality R³

331

0 3 1 — H

332

0 3 1 — H

333

0 3 1 — H

334

0 3 1 — H

335

0 3 1 — H

336

0 3 1 — H

337

0 3 1 — H

338

0 3 1 — H

339

0 3 1 R H

340

0 3 1 S H

341

0 3 1 — H

TABLE 1.32 Compd. No.

k m n chirality R³

342

0 3 1 — H

343

0 3 1 — H

344

0 3 1 — H

345

0 3 1 — H

346

0 3 1 — H

347

0 3 1 — H

348

0 3 1 — H

349

0 3 1 — H

350

0 3 1 — H

351

0 3 1 — H

352

0 3 1 — H

TABLE 1.33 Compd. No.

k m n chirality R³

353

1 2 1 — H

354

1 3 0 — H

355

1 3 0 — H

356

1 3 0 — H

357

1 3 0 — H

358

1 3 0 — H

359

1 3 0 — H

360

1 3 0 — H

361

1 3 0 — H

362

1 3 0 — H

363

1 3 0 — H

TABLE 1.34 Compd. No.

k m n chirality R³

364

1 3 0 — H

365

1 3 0 — H

366

1 3 0 — H

367

1 3 0 — H

368

1 3 0 — H

369

1 3 0 — H

370

1 3 0 — H

371

1 3 0 — H

372

1 3 0 — H

373

1 3 0 — H

374

1 3 0 — H

TABLE 1.35 Compd. No.

k m n chirality R³

375

1 3 0 — H

376

1 3 0 — H

377

1 3 0 — H

378

1 3 0 — H

379

1 3 0 — H

380

1 3 0 — H

381

1 3 0 — H

382

1 3 0 — H

383

1 3 0 — H

384

2 2 0 — H

385

2 2 0 — H

TABLE 13.6 Compd. No.

k m n chirality R³

386

2 2 0 — H

387

2 2 0 — H

388

2 2 0 — H

389

2 2 0 — H

390

2 2 0 — H

391

2 2 0 — H

392

2 2 0 — H

393

2 2 0 — H

394

2 2 0 — H

395

2 2 0 — H

396

2 2 0 — H

TABLE 1.37 Compd. No.

k m n chirality R³

397

2 2 0 — H

398

2 2 0 — H

399

2 2 0 — H

400

2 2 0 — H

401

2 2 0 — H

402

2 2 0 — H

403

2 2 0 — H

404

2 2 0 — H

405

2 2 0 — H

406

2 2 0 — H

407

2 2 0 — H

TABLE 1.38 Compd. No.

k m n chirality R³

408

2 2 0 — H

409

2 2 0 — H

410

2 2 0 — H

411

2 2 0 — H

412

2 2 0 — H

413

2 2 0 — H

414

2 2 0 — H

415

2 2 0 — H

416

2 2 0 — H

417

2 2 0 — H

418

2 2 0 — H

TABLE 1.39 Compd. No.

k m n chirality R³

419

2 2 0 — H

420

2 2 0 — H

421

2 2 0 — H

422

2 2 0 — H

423

2 2 0 — H

424

2 2 0 — H

425

2 2 0 — H

426

2 2 0 — H

427

2 2 0 — H

428

2 2 0 — H

429

2 2 0 — H

TABLE 1.40 Compd. No.

k m n chirality R³

430

2 2 0 — H

431

2 2 0 — H

432

2 2 0 — H

433

2 2 0 — H

434

1 3 1 — H

435

1 3 1 — H

436

1 3 1 — H

437

1 3 1 — H

438

1 3 1 — H

439

1 3 1 — H

440

1 3 1 — H

TABLE 1.41 Compd. No.

k m n chirality R³

441

1 3 1 — H

442

1 3 1 — H

443

1 3 1 — H

444

1 3 1 — H

445

1 3 1 — H

446

1 3 1 — H

447

1 3 1 — H

448

1 3 1 — H

449

1 3 1 — H

450

1 3 1 — H

451

1 3 1 — H

TABLE 1.42 Compd. No.

k m n chirality R³

452

1 3 1 — H

453

1 3 1 — H

454

1 3 1 — H

455

1 3 1 — H

456

1 3 1 — H

457

1 3 1 — H

458

2 2 1 — H

459

2 2 1 — H

460

2 2 1 — H

461

2 2 1 — H

462

2 2 1 — H

TABLE 1.43 Compd. No.

k m n chirality R³

463

2 2 1 — H

464

2 2 1 — H

465

2 2 1 — H

466

2 2 1 — H

467

2 2 1 — H

468

2 2 1 — H

469

2 2 1 — H

470

2 2 1 — H

471

2 2 1 — H

472

2 2 1 — H

473

2 2 1 — H

TABLE 1.44 Compd. No.

k m n chirality R³

474

2 2 1 — H

475

2 2 1 — H

476

2 2 1 — H

477

2 2 1 — H

478

2 2 1 — H

479

2 2 1 — H

480

2 2 1 — H

481

2 2 1 — H

482

2 2 1 — H

483

2 2 1 — H

484

2 2 1 — H

TABLE 1.45 Compd. No.

k m n chirality R³

485

2 2 1 — H

486

2 2 1 — H

487

2 2 1 — H

488

2 2 1 — H

489

2 2 1 — H

490

2 2 1 — H

491

2 2 1 — H

492

2 2 1 — H

493

2 2 1 — H

494

2 2 1 — H

495

2 2 1 — H

TABLE 1.46 Compd. No.

k m n chirality R³

496

2 2 1 — H

497

2 2 1 — H

498

2 2 1 — H

499

2 2 1 — H

500

2 2 1 — H

501

2 2 1 — H

502

2 2 1 — H

503

2 2 1 — H

504

2 2 1 — H

505

2 2 1 — H

506

2 2 1 — H

TABLE 1.47 Compd. No.

k m n chirality R³

507

2 2 1 — H

508

2 2 1 — H

509

2 2 1 — H

510

2 2 1 — H

511

2 2 1 — H

512

2 2 1 — H

513

2 2 1 — H

514

2 2 1 — H

515

2 2 1 — H

516

2 2 1 — H

517

2 2 1 — H

TABLE 1.48       Compd. No.

      k       m       n       chirality 518

2 2 1 — 519

2 2 1 — 520

2 2 1 — 521

2 2 1 — 522

2 2 1 — 523

2 2 1 — 524

2 2 1 — 525

2 2 1 — 526

2 2 1 — 527

2 2 1 — 528

2 2 1 —         Compd. No.         R³

518 H

519 H

520 —CH₃

521

522

523

524

525 H

526 H

527 H

528 H

TABLE 1.49 Compd. No.

k m n chirality R³

529

2 2 1 — H

530

2 2 1 — H

531

2 2 1 — H

532

2 2 1 — H

533

2 2 1 — H

534

2 2 1 — H

535

2 2 1 — H

536

2 2 1 — H

537

2 2 1 — H

538

2 2 1 — H

539

2 2 1 — H

TABLE 1.50 Compd. No.

k m n chirality R³

540

2 2 1 — H

541

2 2 1 — H

542

2 2 1 — H

543

2 2 1 — H

544

2 2 1 — H

545

2 2 1 — H

546

2 2 1 — H

547

2 2 1 — H

548

2 2 1 — H

549

2 2 1 — H

550

2 2 1 — H

TABLE 1.51 Compd. No.

k m n chirality R³

551

2 2 1 — H

552

2 2 1 — H

553

2 2 1 — H

554

2 2 1 — H

555

2 2 1 — H

556

2 2 1 — H

557

2 2 1 — H

558

2 2 1 — H

559

2 2 1 — H

560

2 2 1 — H

561

2 2 1 — H

TABLE 1.52 Compd. No.

k m n chirality R³

562

2 2 1 — H

563

2 2 1 — H

564

2 2 1 — H

565

2 2 1 — H

566

2 2 1 — H

567

2 2 1 — H

568

2 2 1 — H

569

2 2 1 — H

570

2 2 1 — H

571

2 2 1 — H

572

2 2 1 — H

TABLE 1.53 Compd. No.

k m n chirality R³

573

2 2 1 — H

574

2 2 1 — H

575

2 2 1 — H

576

2 2 1 — H

577

2 2 1 — H

578

2 2 1 — H

579

2 2 1 — H

580

2 2 1 — H

581

2 2 1 — H

582

2 2 1 — H

583

2 2 1 — H

TABLE 1.54 Compd. No.

k m n chirality R³

584

2 2 1 — H

585

2 2 1 — H

586

2 2 1 — H

587

2 2 1 — H

588

2 2 1 — H

589

2 2 1 — H

590

2 2 1 — H

591

2 2 1 — H

592

2 2 1 — H

593

2 2 1 — H

594

2 2 1 — H

TABLE 1.55 Compd. No.

k m n chirality R³

595

2 2 1 — H

596

2 2 1 — H

597

2 2 1 — H

598

2 2 1 — H

599

2 2 1 — H

600

2 2 1 — H

601

2 2 1 — H

602

2 2 1 — H

603

2 2 1 — H

604

2 2 1 — H

605

2 2 1 — H

TABLE 1.56 Compd. No.

k m n chirality R³

606

2 2 1 — H

607

2 2 1 — H

608

2 2 1 — H

609

2 2 1 — H

610

2 2 1 — H

611

2 2 1 — H

612

2 2 1 — H

613

2 2 1 — H

614

2 2 1 — H

615

2 2 1 — H

616

2 2 1 — H

TABLE 1.57 Compd. No.

k m n chirality R³

617

2 2 1 — H

618

2 2 1 — H

619

2 2 1 — H

620

2 2 1 — H

621

2 2 1 — H

622

2 2 1 — H

623

2 2 1 — H

624

2 2 1 — H

625

2 2 1 — H

626

2 2 1 — H

627

2 2 1 — H

TABLE 1.58 Compd. No.

k m n chirality R³

628

2 2 1 — H

629

2 2 1 — H

630

2 2 1 — H

631

2 2 1 — H

632

2 2 1 — H

633

2 2 1 — H

634

2 2 1 — H

635

2 2 1 — H

636

2 2 1 — H

637

2 2 1 — H

638

2 2 1 — H

TABLE 1.59 Compd. No.

k m n chirality R³

639

2 2 1 — H

640

2 2 1 — H

641

2 2 1 — H

642

2 2 1 — H

643

2 2 1 — H

644

2 2 1 — H

645

2 2 1 — H

646

2 2 1 — H

647

2 2 1 — H

648

2 2 1 — H

649

2 2 1 — H

TABLE 1.60 Compd. No.

k m n chirality R³

650

2 2 1 — H

651

2 2 1 — H

652

2 2 1 — H

653

2 2 1 — H

654

2 2 1 — H

655

2 2 1 — H

656

2 2 1 — H

657

2 2 1 — H

658

2 2 1 — H

659

2 2 1 — H

660

2 2 1 — H

TABLE 1.61 Compd. No.

k m n chirality R³

661

2 2 1 — H

662

2 2 1 — H

663

2 2 1 — H

664

2 2 1 — H

665

2 2 1 — H

666

2 2 1 — H

667

2 2 1 — H

668

2 2 1 — H

669

2 2 1 — H

670

2 2 1 — H

671

2 2 1 — H

TABLE 1.62 Compd. No.

k m n chirality R³

672

2 2 1 — H

673

2 2 1 — H

674

2 2 1 — H

675

2 2 1 — H

676

2 2 1 — H

677

2 2 1 — H

678

2 2 1 — H

679

2 2 1 — H

680

2 2 1 — H

681

2 2 1 — H

682

2 2 1 — H

TABLE 1.63 Compd. No.

k m n chirality R³

683

2 2 1 — H

684

2 2 1 — H

685

2 2 1 — H

686

2 2 1 — H

687

2 2 1 — H

688

2 2 1 — H

689

2 2 1 — H

690

2 2 1 — H

691

2 2 1 — H

692

2 2 1 — H

693

2 2 1 — H

TABLE 1.64 Compd. No.

k m n chirality R³

694

2 2 1 — H

695

2 2 1 — H

696

2 2 1 — H

697

2 2 1 — H

698

2 2 1 — H

699

2 2 1 — H

700

2 2 1 — H

701

2 2 1 — H

702

2 2 1 — H

703

2 2 1 — H

704

2 2 1 — H

TABLE 1.65 Compd. No.

k m n chirality R³

705

2 2 1 — H

706

2 2 1 — H

707

2 2 1 — H

708

2 2 1 — H

709

2 2 1 — H

710

2 2 1 — H

711

2 2 1 — H

712

2 2 1 — H

713

2 2 1 — H

714

2 2 1 — H

715

2 2 1 — H

TABLE 1.66 Compd. No.

k m n chirality R³

716

2 2 1 — H

717

2 2 1 — H

718

2 2 1 — H

719

2 2 1 — H

720

2 2 1 — H

721

2 2 1 — H

722

2 2 1 — H

723

2 2 1 — H

724

2 2 1 — H

725

2 2 1 — H

726

2 2 1 — H

TABLE 1.67 Compd. No.

k m n chirality R³

727

2 2 1 — H

728

2 2 1 — H

729

2 2 1 — H

730

2 2 1 — H

731

2 2 1 — H

732

2 2 1 — H

733

2 2 1 — H

734

2 2 1 — H

735

2 2 1 — H

736

2 2 1 — H

737

2 2 1 — H

TABLE 1.68 Compd. No.

k m n chirality R³

738

2 2 1 — H

739

2 2 1 — H

740

2 2 1 — H

741

2 2 1 — H

742

2 2 1 — H

743

2 2 1 — H

744

2 2 1 — H

745

2 2 1 — H

746

2 2 1 — H

747

2 2 1 — H

748

2 2 1 — H

TABLE 1.69 Compd. No.

k m n chirality R³

749

2 2 1 — H

750

2 2 1 — H

751

2 2 1 — H

752

2 2 1 — H

753

2 2 1 — H

754

2 2 1 — H

755

2 2 1 — H

756

2 2 1 — H

757

2 2 1 — H

758

2 2 1 — H

759

2 2 1 — H

TABLE 1.70 Compd. No.

k m n chirality R³

760

2 2 1 — H

761

2 2 1 — H

762

2 2 1 — H

763

2 2 1 — H

764

2 2 1 — H

765

2 2 1 — H

766

2 2 1 — H

767

2 2 1 — H

768

2 2 1 — H

769

2 2 1 — H

770

2 2 1 — H

TABLE 1.71 Compd. No.

k m n chirality R³

771

2 2 1 — H

772

2 2 1 — H

773

2 2 1 — H

774

2 2 1 — H

775

2 2 1 — H

776

2 2 1 — H

777

2 2 1 — H

778

2 2 1 — H

779

2 2 1 — H

780

2 2 1 — H

781

2 2 1 — H

TABLE 1.72 Compd. No.

k m n chirality R³

782

2 2 1 — H

783

2 2 1 — H

784

2 2 1 — H

785

2 2 1 — H

786

2 2 1 — H

787

2 2 1 — H

788

2 2 1 — H

789

2 2 1 — H

790

2 2 1 — H

791

2 2 1 — H

792

2 2 1 — H

TABLE 1.73 Compd. No.

k m n chirality R³

793

2 2 1 — H

794

2 2 1 — H

795

2 2 1 — H

796

2 2 1 — H

797

2 2 1 — H

798

2 2 1 — H

799

2 2 1 — H

800

2 2 1 — H

801

2 2 1 — H

802

2 2 1 — H

803

2 2 1 — H

TABLE 1.74 Compd. No.

k m n chirality R³

804

2 2 1 — H

805

2 2 1 — H

806

2 2 1 — H

807

2 2 1 — H

808

2 2 1 — H

809

2 2 1 — H

810

2 2 1 — H

811

2 2 1 — H

812

2 2 1 — H

813

2 2 1 — H

814

2 2 1 — H

TABLE 1.75 Compd. No.

k m n chirality R³

815

2 2 1 — H

816

2 2 1 — H

817

2 2 1 — H

818

2 2 1 — H

819

2 2 1 — H

820

2 2 1 — H

821

2 2 1 — H

822

2 2 1 — H

823

2 2 1 — H

824

2 2 1 — H

825

2 2 1 — H

TABLE 1.76 Compd. No.

k m n chirality R³

826

2 2 1 — H

827

2 2 1 — H

828

2 2 1 — H

829

2 2 1 — H

830

2 2 1 — H

831

2 2 1 — H

832

2 2 1 — H

833

2 2 1 — H

834

2 2 1 — H

835

2 2 1 — H

836

2 2 1 — H

TABLE 1.77 Compd. No.

k m n chirality R³

837

2 2 1 — H

838

2 2 1 — H

839

2 2 1 — H

840

2 2 1 — H

841

2 2 1 — H

842

2 2 1 — H

843

2 2 1 — H

844

2 2 1 — H

845

2 2 1 — H

846

2 2 1 — H

847

2 2 1 — H

TABLE 1.78 Compd. No.

k m n chirality R³

848

2 2 1 — H

849

2 2 1 — H

850

2 2 1 — H

851

2 2 1 — H

852

2 2 1 — H

853

2 2 1 — H

854

2 2 1 — H

855

2 2 1 — H

856

2 2 1 — H

857

2 2 1 — H

858

2 2 1 — H

TABLE 1.79 Compd. No.

k m n chirality R³

859

2 2 1 — H

860

2 2 1 — H

861

2 2 1 — H

862

2 2 1 — H

863

2 2 1 — H

864

2 2 1 — H

865

2 2 1 — H

866

2 2 1 — H

867

2 2 1 — H

868

2 2 1 — H

869

2 2 1 — H

TABLE 1.80 Compd. No.

k m n chirality R³

870

2 2 1 — H

871

2 2 1 — H

872

2 2 1 — H

873

2 2 1 — H

874

2 2 1 — H

875

2 2 1 — H

876

2 2 1 — H

877

2 2 1 — H

878

2 2 1 — H

879

2 2 1 — H

880

2 2 1 — H

TABLE 1.81 Compd. No.

k m n chirality R³

881

2 2 1 — H

882

2 2 1 — H

883

2 2 1 — H

884

2 2 1 — H

885

2 2 1 — H

886

2 2 1 — H

887

2 2 1 — H

888

2 2 1 — H

889

2 2 1 — H

890

2 2 1 — H

891

2 2 1 — H

TABLE 1.82 Compd. No.

k m n chirality R³

892

2 2 1 — H

893

2 2 1 — H

894

2 2 1 — H

895

2 2 1 — H

896

2 2 1 — H

897

2 2 1 — H

898

2 2 1 — H

899

2 2 1 — H

900

2 2 1 — H

901

2 2 1 — H

902

2 2 1 — H

TABLE 1.83 Compd. No.

k m n chirality R³

903

2 2 1 — H

904

2 2 1 — H

905

2 2 1 — H

906

2 2 1 — H

907

2 2 1 — H

908

2 2 1 — H

909

2 2 1 — H

910

2 2 1 — H

911

2 2 1 — H

912

2 2 1 — H

913

2 2 1 — H

TABLE 1.84 Compd. No.

k m n chirality R³

914

2 2 1 — H

915

2 2 1 — H

916

2 2 1 — H

917

2 2 1 — H

918

2 2 1 — H

919

2 2 1 — H

920

2 2 1 — H

921

2 2 1 — H

922

2 2 1 — H

923

2 2 1 — H

924

2 2 1 — H

TABLE 1.85 Compd. No.

k m n chirality R³

925

2 2 1 — H

926

2 2 1 — H

927

2 2 1 — H

928

2 2 1 — H

929

2 2 1 — H

930

2 2 1 — H

931

2 2 1 — H

932

2 2 1 — H

933

2 2 1 — H

934

2 2 1 — H

935

2 2 1 — H

TABLE 1.86 Compd. No.

k m n chirality R³

936

2 2 1 — H

937

2 2 1 — H

938

2 2 1 — H

939

2 2 1 — H

940

2 2 1 — H

941

2 2 1 — H

942

2 2 1 — H

943

1 4 0 — H

944

1 4 0 — H

945

1 4 0 — H

946

1 4 0 — H

TABLE 1.87 Compd. No.

k m n chirality R³

947

1 4 0 — H

948

1 4 0 — H

949

1 4 0 — H

950

0 4 1 — H

951

1 2 0 R H

952

1 2 0 R H

953

1 2 0 R H

954

1 2 0 R H

955

1 2 0 R H

956

1 2 0 R H

957

1 2 0 R H

TABLE 1.88 Compd. No.

k m n chirality R³

958

1 2 0 R H

959

1 2 0 R H

960

1 2 0 R H

961

1 2 0 R H

962

1 2 0 R H

963

1 2 0 R H

964

1 2 0 R H

965

1 2 0 R H

966

1 2 0 R H

967

1 2 0 R H

968

1 2 0 R H

TABLE 1.89 Compd. No.

k m n chirality R³

969

1 2 0 R H

970

1 2 0 R H

971

1 2 0 R H

972

1 2 0 R H

973

1 2 0 R H

974

1 2 0 R H

975

1 2 0 R H

976

1 2 0 R H

977

1 2 0 R H

978

1 2 0 R H

979

1 2 0 R H

TABLE 1.90 Compd. No.

k m n chirality R³

980

1 2 0 R H

981

1 2 0 R H

982

1 2 0 R H

983

1 2 0 R H

984

1 2 0 R H

985

1 2 0 R H

986

1 2 0 R H

987

2 2 1 — H

988

1 4 0 — H

989

1 4 0 — H

990

1 4 0 — H

TABLE 1.91 Compd. No.

k m n chirality R³

991

1 4 0 — H

992

1 4 0 — H

993

1 4 0 — H

994

1 4 0 — H

995

1 4 0 — H

996

1 4 0 — H

997

2 2 1 — H

998

2 2 1 — H

999

2 2 1 — H

1000 

2 2 1 — H

1001 

2 2 1 — H

TABLE 1.92 Compd. No.

k m n chirality R³

1002

2 2 1 — H

1003

2 2 1 — H

1004

2 2 1 — H

1005

2 2 1 — H

1006

2 2 1 — H

1007

2 2 1 — H

1008

2 2 1 — H

1009

2 2 1 — H

1010

2 2 1 — H

1011

2 2 1 — H

1012

2 2 1 — H

TABLE 1.93 Compd. No.

k m n chirality R³

1013

2 2 1 — H

1014

2 2 1 — H

1015

2 2 1 — H

1016

2 2 0 — H

1017

2 2 0 — H

1018

2 2 1 — H

1019

2 2 1 — H

1020

2 2 1 — H

1021

2 2 1 — H

1022

2 2 1 — H

1023

2 2 1 — H

TABLE 1.94 Compd. No.

k m n chirality R³

1024

2 2 1 — H

1025

2 2 1 — H

1026

2 2 1 — H

1027

2 2 1 — H

1028

2 2 1 — H

1029

2 2 1 — H

1030

2 2 1 — H

1031

2 2 1 — H

1032

2 2 1 — H

1033

2 2 1 — H

1034

2 2 1 — H

TABLE 1.95 Compd. No.

k m n chirality R³

1035

2 2 1 — H

1036

2 2 1 — H

1037

2 2 1 — H

1038

2 2 1 — H

1039

2 2 1 — H

1040

2 2 1 — H

1041

2 2 1 — H

1042

2 2 1 — H

1043

2 2 1 — H

1044

2 2 1 — H

1045

2 2 1 — H

TABLE 1.96 Compd. No.

k m n chirality R³

1046

2 2 1 — H

1047

2 2 1 — H

1048

2 2 1 — H

1049

2 2 1 — H

1050

2 2 1 — H

1051

2 2 1 — H

1052

2 2 1 — H

1053

2 2 1 — H

1054

2 2 1 — H

1055

2 2 1 — H

1056

2 2 1 — H

TABLE 1.97 Compd. No.

k m n chirality R³

1057

2 2 1 — H

1058

2 2 1 — H

1059

2 2 1 — H

1060

2 2 1 — H

1061

2 2 1 — H

1062

2 2 1 — H

1063

2 2 1 — H

1064

2 2 1 — H

1065

2 2 1 — H

1066

2 2 1 — H

1067

2 2 1 — H

TABLE 1.98 Compd. No.

k m n chirality R³

1068

2 2 1 — H

1069

2 2 1 — H

1070

2 2 1 — H

1071

2 2 1 — H

1072

2 2 1 — H

1073

2 2 1 — H

1074

2 2 1 — H

1075

2 2 1 — H

1076

2 2 1 — H

1077

2 2 1 — H

1078

2 2 1 — H

TABLE 1.99 Compd. No.

k m n chirality R³

1079

2 2 1 — H

1080

2 2 1 — H

1081

2 2 1 — H

1082

2 2 1 — H

1083

2 2 1 — H

1084

1 2 0 R H

1085

1 2 0 R H

1086

1 2 0 R H

1087

1 2 0 R H

1088

1 2 0 R H

1089

1 2 0 R H

TABLE 1.100 Compd. No.

k m n chirality R³

1090

1 2 0 R H

1091

1 2 0 R H

1092

1 2 0 R H

1093

1 2 0 R H

1094

1 2 0 R H

1095

1 2 0 R H

1096

1 2 0 R H

1097

1 2 0 R H

1098

1 2 0 R H

1099

1 2 0 R H

1100

1 2 0 R H

TABLE 1.101 Compd. No.

k m n chirality R³

1101

1 2 0 R H

1102

1 2 0 R H

1103

1 2 0 R H

1104

1 2 0 R H

1105

1 2 0 R H

1106

1 2 0 R H

1107

1 2 0 R H

1108

1 2 0 R H

1109

1 2 0 R H

1110

1 2 0 R H

1111

1 2 0 R H

TABLE 1.102 Compd. No.

k m n chirality R³

1112

1 2 0 R H

1113

2 2 1 — H

1114

2 2 1 — H

1115

2 2 1 — H

1116

2 2 1 — H

1117

2 2 1 — H

1118

1 2 0 R H

1119

1 2 0 R H

1120

1 2 0 R H

1121

1 2 0 R H

1122

1 2 0 R H

TABLE 1.103 Compd. No.

k m n chirality R³

1123

1 2 0 R H

1124

1 2 0 R H

1125

2 2 1 — H

1126

2 2 1 — H

1127

2 2 1 — H

1128

2 2 1 — H

1129

2 2 1 — H

1130

2 2 1 — H

1131

2 2 1 — H

1132

2 2 1 — H

1133

1 2 0 R H

TABLE 1.104 Compd. No.

k m n chirality R³

1134

1 2 0 R H

1135

1 2 0 R H

1136

1 2 0 R H

1137

1 2 0 R H

1138

1 2 0 R H

1139

1 2 0 R H

1140

1 2 0 R H

1141

1 2 0 R H

1142

1 2 0 R H

1143

1 2 0 R H

1144

1 2 0 R H

TABLE 1.105 Compd. No.

k m n chirality R³

1145

1 2 0 R H

1146

1 2 0 R H

1147

1 2 0 R H

1148

1 2 0 R H

1149

1 2 0 R H

1150

1 2 0 R H

1151

1 2 0 R H

1152

1 2 0 R H

1153

1 2 0 R H

1154

1 2 0 R H

1155

1 2 0 R H

TABLE 1.106 Compd. No.

k m n chirality R³

1156

1 2 0 R H

1157

1 2 0 R H

1158

1 2 0 R H

1159

1 2 0 R H

1160

1 2 0 R H

1161

1 2 0 R H

1162

1 2 0 R H

1163

1 2 0 R H

1164

1 2 0 R H

1165

1 2 0 R H

1166

1 2 0 R H

TABLE 1.107 Compd. No.

k m n chirality R³

1167

2 2 1 — H

1168

1 2 0 R H

1169

1 2 0 R H

1170

1 2 0 R H

1171

1 2 0 R H

1172

1 2 0 R H

1173

1 2 0 R H

1174

1 2 0 R H

1175

1 2 0 R H

1176

1 2 0 R H

1177

1 2 0 R H

TABLE 1.108 Compd. No.

k m n chirality R³

1178

1 2 0 R H

1179

1 2 0 R H

1180

1 2 0 R H

1181

1 2 0 R H

1182

1 2 0 R H

1183

1 2 0 R H

1184

1 2 0 R H

1185

1 2 0 R H

1186

1 2 0 R H

1187

2 2 1 — H

1188

2 2 1 — H

TABLE 1.109 Compd. No.

k m n chirality R³

1189

2 2 1 — H

1190

2 2 1 — H

1191

1 2 0 R H

1192

1 2 0 R H

1193

1 2 0 R H

1194

1 2 0 R H

1195

1 2 0 R H

1196

1 2 0 R H

1197

1 2 0 R H

1198

1 2 0 R H

1199

1 2 0 R H

TABLE 1.110 Compd. No.

k m n chirality R³

1200

1 2 0 R H

1201

1 2 0 R H

1202

1 2 0 R H

1203

1 2 0 R H

1204

1 2 0 R H

1205

1 2 0 R H

1206

1 2 0 R H

1207

1 2 0 R H

1208

1 2 0 R H

1209

1 2 0 R H

1210

1 2 0 R H

TABLE 1.111 Compd. No.

k m n chirality R³

1211

1 2 0 R H

1212

1 2 0 R H

1213

2 2 1 — H

1214

2 2 1 — H

1215

2 2 1 — H

1216

2 2 1 — H

1217

1 2 0 R H

1218

1 2 0 R H

1219

1 2 0 R H

1220

1 2 0 R H

1221

1 2 0 R H

TABLE 1.112 Compd. No.

k m n chirality R³

1222

1 2 0 R H

1223

1 2 0 R H

1224

1 2 0 R H

1225

1 2 0 R H

1226

1 2 0 R H

1227

1 2 0 R H

1228

1 2 0 R H

1229

1 2 0 R H

1230

1 2 0 R H

1231

1 2 0 R H

1232

1 2 0 R H

TABLE 1.113 Compd. No.

k m n chirality R³

1233

1 2 0 R H

1234

1 2 0 R H

1235

1 2 0 R H

1236

1 2 0 R H

1237

1 2 0 R H

1238

1 2 0 R H

1239

1 2 0 R H

1240

1 2 0 R H

1241

2 2 1 — H

1242

2 2 1 — H

1243

2 2 1 — H

TABLE 1.114 Compd. No.

k m n chirality R³

1244

2 2 1 — H

1245

2 2 1 — H

1246

2 2 1 — H

1247

2 2 1 — H

1248

2 2 1 — H

1249

1 2 0 R H

1250

1 2 0 R H

1251

1 2 0 R H

1252

1 2 0 R H

1253

1 2 0 R H

1254

1 2 0 R H

TABLE 1.115 Compd. No.

k m n chirality R³

1255

1 2 0 R H

1256

1 2 0 R H

1257

1 2 0 R H

1258

1 2 0 R H

1259

1 2 0 R H

1260

1 2 0 R H

1261

1 2 0 R H

1262

1 2 0 R H

1263

1 2 0 R H

1264

1 2 0 R H

1265

1 2 0 R H

TABLE 1.116 Compd. No.

k m n chirality R³

1266

1 2 0 R H

1267

1 2 0 R H

1268

1 2 0 R H

1269

1 2 0 R H

1270

1 2 0 R H

1271

1 2 0 R H

1272

1 2 0 R H

1273

1 2 0 R H

1274

1 2 0 R H

1275

1 2 0 R H

1276

1 2 0 R H

TABLE 1.117 Compd. No.

k m n chirality R³

1277

1 2 0 R H

1278

1 2 0 R H

1279

1 2 0 R H

1280

1 2 0 R H

1281

1 2 0 R H

1282

2 2 1 — H

1283

2 2 1 — H

1284

2 2 1 — H

1285

2 2 1 — H

1286

1 2 0 R H

1287

1 2 0 R H

TABLE 1.118 Compd. No.

k m n chirality R³

1288

1 2 0 R H

1289

1 2 0 R H

1290

1 2 0 R H

1291

1 2 0 R H

1292

1 2 0 R H

1293

1 2 0 R H

1294

1 2 0 R H

1295

1 2 0 R H

1296

1 2 0 R H

1297

1 2 0 R H

1298

1 2 0 R H

TABLE 1.119 Compd. No.

k m n chirality R³

1299

1 2 0 R H

1300

1 2 0 R H

1301

1 2 0 R H

1302

1 2 0 R H

1303

1 2 0 R H

1304

1 2 0 R H

1305

1 2 0 R H

1306

1 2 0 R H

1307

1 2 0 R H

1308

1 2 0 R H

1309

1 2 0 R H

TABLE 1.120 Compd. No.

k m n chirality R³

1310

1 2 0 R H

1311

1 2 0 R H

1312

1 2 0 R H

1313

1 2 0 R H

1314

1 2 0 R H

1315

1 2 0 R H

1316

1 2 0 R H

1317

1 2 0 R H

1318

1 2 0 R H

1319

1 2 0 R H

1320

1 2 0 R H

TABLE 1.121 Compd. No.

k m n chirality R³

1321

1 2 0 R H

1322

1 2 0 R H

1323

1 2 0 R H

1324

1 2 0 R H

1325

1 2 0 R H

1326

1 2 0 R H

1327

1 2 0 R H

1328

1 2 0 R H

1329

1 2 0 R H

1330

1 2 0 R H

1331

1 2 0 R H

TABLE 1.122 Compd. No.

k m n chirality R³

1332

1 2 0 R H

1333

1 2 0 R H

1334

1 2 0 R H

1335

1 2 0 R H

1336

1 2 0 R H

1337

1 2 0 R H

1338

1 2 0 R H

1339

1 2 0 R H

1340

1 2 0 R H

1341

1 2 0 R H

1342

2 2 1 — H

TABLE 1.123 Compd. No.

k m n chirality R³

1343

2 2 1 — H

1344

2 2 1 — H

1345

2 2 1 — H

1346

2 2 1 — H

1347

1 2 0 R H

1348

1 2 0 R H

1349

1 2 0 R H

1350

2 2 1 — H

1351

1 2 0 R H

1352

1 2 0 R H

1353

1 2 0 R H

TABLE 1.124 Compd. No.

k m n chirality R³

1354

2 2 1 — H

1355

1 2 0 R H

1356

1 2 0 R H

1357

1 2 0 R H

1358

2 2 1 — H

1359

1 2 0 R H

1360

1 2 0 R H

1361

1 2 0 R H

1362

1 2 0 R H

1363

1 2 0 R H

1364

1 2 0 R H

TABLE 1.125 Compd. No.

k m n chirality R³

1365

1 2 0 R H

1366

1 2 0 R H

1367

1 2 0 R H

1368

1 2 0 R H

1369

1 2 0 R H

1370

1 2 0 R H

1371

1 2 0 R H

1372

1 2 0 R H

1373

1 2 0 R H

1374

1 2 0 R H

1375

1 2 0 R H

TABLE 1.126 Compd. No.

k m n chirality R³

1376

1 2 0 R H

1377

1 2 0 R H

1378

1 2 0 R H

1379

1 2 0 R H

1380

1 2 0 R H

1381

1 2 0 R H

1382

1 2 0 R H

1383

2 2 1 — H

1384

2 2 1 — H

1385

2 2 1 — H

1386

2 2 1 — H

TABLE 1.127 Compd. No.

k m n chirality R³

1387

1 2 0 R H

1388

1 2 0 R H

1389

1 2 0 R H

1390

1 2 0 R H

1391

1 2 0 R H

1392

1 2 0 R H

1393

1 2 0 R H

1394

1 2 0 R H

1395

1 2 0 R H

1396

1 2 0 R H

1397

1 2 0 R H

TABLE 1.128 Compd. No.

k m n chirality R³

1398

1 2 0 R H

1399

1 2 0 R H

1400

1 2 0 R H

1401

1 2 0 R H

1402

1 2 0 R H

1403

1 2 0 R H

1404

1 2 0 R H

1405

1 2 0 R H

1406

1 2 0 R H

1407

1 2 0 R H

1408

1 2 0 R H

TABLE 1.129 Compd. No.

k m n chirality R³

1409

1 2 0 R H

1410

1 2 0 R H

1411

1 2 0 R H

1412

1 2 0 R H

1413

1 2 0 R H

1414

2 2 1 — H

1415

1 2 0 R H

1416

1 2 0 R H

1417

1 2 0 R H

1418

2 2 1 — H

1419

1 2 0 R H

TABLE 1.130 Compd. No.

k m n chirality R³

1420

1 2 0 R H

1421

1 2 0 R H

1422

2 2 1 — H

1423

1 2 0 R H

1424

1 2 0 R H

1425

1 2 0 R H

1426

2 2 1 — H

1427

2 2 1 — H

1428

2 2 1 — H

1429

2 2 1 — H

1430

2 2 1 — H

TABLE 1.131 Compd. No.

k m n chirality R³

1431

2 2 1 — H

1432

2 2 1 — H

1433

2 2 1 — H

1434

2 2 1 — H

1435

2 2 1 — H

1436

2 2 1 — H

1437

2 2 1 — H

1438

2 2 1 — H

1439

2 2 1 — H

1440

2 2 1 — H

1441

2 2 1 — H

TABLE 1.132 Compd. No.

k m n chirality R³

1442

2 2 1 — H

1443

2 2 1 — H

1444

2 2 1 — H

1445

2 2 1 — H

1446

2 2 1 — H

1447

2 2 1 — H

1448

2 2 1 — H

1449

2 2 1 — H

1450

2 2 1 — H

1451

2 2 1 — H

1452

2 2 1 — H

TABLE 1.133 Compd. No.

k m n chirality R³

1453

2 2 1 — H

1454

2 2 1 — H

1455

2 2 1 — H

1456

2 2 1 — H

1457

2 2 1 — H

1458

2 2 1 — H

1459

2 2 1 — H

1460

2 2 1 — H

1461

2 2 1 — H

1462

2 2 1 — H

1463

2 1 1 — H

TABLE 1.134 Compd. No.

k m n chirality R³

1464

2 1 1 — H

1465

2 1 1 — H

1466

2 1 1 — H

1467

2 1 1 — H

1468

2 1 1 — H

1469

2 1 1 — H

1470

2 1 1 — H

1471

2 1 1 — H

1472

1 2 0 R H

1473

1 2 0 R H

1474

1 2 0 R H

TABLE 1.135 Compd. No.

k m n chirality R³

1475

1 2 0 R H

1476

1 2 0 R H

1477

1 2 0 R H

1478

1 2 0 R H

1479

1 2 0 R H

1480

1 2 0 R H

1481

1 2 0 R H

1482

1 2 0 R H

1483

1 2 0 R H

1484

1 2 0 R H

1485

1 2 0 R H

TABLE 1.136 Compd. No.

k m n chirality R³

1486

1 2 0 R H

1487

1 2 0 R H

1488

1 2 0 R H

1489

1 2 0 R H

1490

1 2 0 R H

1491

1 2 0 R H

1492

1 2 0 R H

1493

1 2 0 R H

1494

1 2 0 R H

1495

1 2 0 R H

1496

1 2 0 R H

TABLE 1.137 Compd. No.

k m n chirality R³

1497

1 2 0 R H

1498

1 2 0 R H

1499

1 2 0 R H

1500

1 2 0 R H

1501

1 2 0 R H

1502

1 2 0 R H

1503

1 2 0 R H

1504

1 2 0 R H

1505

1 2 0 R H

1506

2 1 1 — H

1507

2 1 1 — H

TABLE 1.138 Compd. No.

k m n chirality R³

1508

2 1 1 — H

1509

2 1 1 — H

1510

2 1 1 — H

1511

2 1 1 — H

1512

2 1 1 — H

1513

2 1 1 — H

1514

2 2 1 — H

1515

2 2 1 — H

1516

2 2 1 — H

1517

2 2 1 — H

1518

2 2 1 — H

TABLE 1.139 Compd. No.

k m n chirality R³

1519

2 2 1 — H

1520

1 2 0 R H

1521

1 2 0 R H

1522

1 2 0 R H

1523

1 2 0 R H

1524

1 2 0 R H

1525

1 2 0 R H

1526

1 2 0 R H

1527

1 2 0 R H

1528

1 2 0 R H

1529

1 2 0 R H

TABLE 1.140 Compd. No.

k m n chirality R³

1530

1 2 0 R H

1531

1 2 0 R H

1532

1 2 0 R H

1533

1 2 0 R H

1534

1 2 0 R H

1535

1 2 0 R H

1536

1 2 0 R H

1537

1 2 0 R H

1538

1 2 0 R H

1539

1 2 0 R H

1540

1 2 0 R H

TABLE 1.141 Compd. No.

k m n chirality R³

1541

1 2 0 R H

1542

1 2 0 R H

1543

1 2 0 R H

1544

1 2 0 R H

1545

1 2 0 R H

1546

1 2 0 R H

1547

1 2 0 R H

1548

1 2 0 R H

1549

1 2 0 R H

1550

1 2 0 R H

1551

1 2 0 R H

TABLE 1.142 Compd. No.

k m n chirality R³

1552

1 2 0 R H

1553

1 2 0 R H

1554

1 2 0 R H

1555

1 2 0 R H

1556

1 2 0 R H

1557

1 2 0 R H

1558

1 2 0 R H

1559

1 2 0 R H

1560

1 2 0 R H

1561

1 2 0 R H

1562

1 2 0 R H

TABLE 1.143 Com- pd. No.

k m n chir- ality R³

1563

1 2 0 R H

1564

1 2 0 R H

1565

1 2 0 R H

1566

1 2 0 R H

1567

1 2 0 R H

1568

1 2 0 R H

1569

1 2 0 R H

1570

2 2 1 — H

1571

2 2 1 — H

1572

2 2 1 — H

1573

2 2 1 — H

TABLE 1.144 Compd. No.

k m n chirality R³

1574

2 2 1 — H

1575

2 2 1 — H

1576

2 2 1 — H

1577

2 2 1 — H

1578

2 2 1 — H

1579

2 2 1 — H

1580

2 2 1 — H

1581

2 2 1 — H

1582

2 2 1 — H

1583

1 2 0 R H

1584

1 2 0 R H

TABLE 1.145 Compd. No.

k m n chirality R³

1585

1 2 0 R H

1586

1 2 0 R H

1587

1 2 0 R H

1588

1 2 0 R H

1589

1 2 0 R H

1590

1 2 0 R H

1591

1 2 0 R H

1592

1 2 0 R H

1593

1 2 0 R H

1594

1 2 0 R H

1595

1 2 0 R H

TABLE 1.146 Compd. No.

k m n chirality R³

1596

1 2 0 R H

1597

1 2 0 R H

1598

1 2 0 R H

1599

1 2 0 R H

1600

2 2 1 — H

1601

2 2 1 — H

1602

2 2 1 — H

1603

2 2 1 — H

1604

2 2 1 — H

1605

2 2 1 — H

1606

1 2 0 R H

TABLE 1.147 Compd. No.

k m n chirality R³

1607

1 2 0 R H

1608

1 2 0 R H

1609

2 2 1 — H

1610

2 2 1 — H

1611

2 2 1 — H

1612

2 2 1 — H

1613

2 2 1 — H

1614

1 2 0 R H

1615

2 2 1 — H

1616

2 2 1 — H

1617

2 2 1 — H

TABLE 1.148 Compd. No.

k m n chirality R³

1618

1 2 0 R H

1619

1 2 0 R H

1620

1 2 0 R H

1621

1 2 0 R H

1622

1 2 0 R H

1623

1 2 0 R H

1624

1 2 0 R H

1625

1 2 0 R H

1626

1 2 0 R H

1627

1 2 0 R H

1628

1 2 0 R H

TABLD 1.149 Compd. No.

k m n chirality R³

1629

1 2 0 R H

1630

1 2 0 R H

1631

1 2 0 R H

1632

1 2 0 R H

1633

1 2 0 R H

1634

1 2 0 R H

1635

1 2 0 R H

1636

1 2 0 R H

1637

1 2 0 R H

1638

1 2 0 R H

1639

1 2 0 R H

TABLE 1.150 Compd. No.

k m n chirality R³

1640

1 2 0 R H

1641

1 2 0 R H

1642

1 2 0 R H

1643

1 2 0 R H

1644

1 2 0 R H

1645

1 2 0 R H

1646

1 2 0 R H

1647

2 2 1 — H

1648

1 2 0 R H

1649

2 2 1 — H

1650

1 2 0 R H

TABLE 1.151 Compd. No.

k m n chirality R³

1651

2 2 1 — H

1652

2 2 1 — H

1653

2 2 1 — H

1654

2 2 1 — H

1655

2 2 1 — H

1656

2 2 1 — H

1657

2 2 1 — H

1658

2 2 1 — H

1659

2 2 1 — H

1660

1 2 0 R H

1661

1 2 0 R H

TABLE 1.152 Compd. No.

k m n chirality R³

1662

1 2 0 R H

1663

1 2 0 R H

1664

2 2 1 — H

1665

2 2 1 — H

1666

2 2 1 — H

1667

2 2 1 — H

1668

2 2 1 — H

1669

2 2 1 — H

1670

2 2 1 — H

1671

2 2 1 — H

1672

2 2 1 — H

TABLE 1.153 Compd. No.

k m n chirality R³

1673

2 2 1 — H

1674

2 2 1 — H

1675

2 2 1 — H

1676

2 2 1 — H

1677

2 2 1 — H

1678

2 2 1 — H

1679

2 2 1 — H

1680

2 2 1 — H

1681

2 2 1 — H

1682

2 2 1 — H

1683

2 2 1 — H

TABLE 1.154 Compd. No.

k m n chirality R³

1684

2 2 1 — H

1685

2 2 1 — H

1686

2 2 1 — H

1687

2 2 1 — H

1688

2 2 1 — H

1689

2 2 1 — H

1690

2 2 1 — H

1691

2 2 1 — H

1692

1 2 0 R H

1693

1 2 0 R H

1694

1 2 0 R H

TABLE 1.155 Compd. No.

k m n chirality R³

1695

1 2 0 R H

1696

1 2 0 R H

1697

1 2 0 R H

1698

1 2 0 R H

1699

1 2 0 R H

1700

1 2 0 R H

1701

1 2 0 R H

1702

1 2 0 R H

1703

1 2 0 R H

1704

1 2 0 R H

1705

1 2 0 R H

TABLE 1.156 Compd. No.

k m n chirality R³

1706

1 2 0 R H

1707

1 2 0 R H

1708

1 2 0 R H

1709

1 2 0 R H

1710

1 2 0 R H

1711

1 2 0 R H

1712

1 2 0 R H

1713

1 2 0 R H

1714

1 2 0 R H

1715

1 2 0 R H

1716

1 2 0 R H

TABLE 1.157 Compd. No.

k m n chirality R³

1717

1 2 0 R H

1718

1 2 0 R H

1719

1 2 0 R H

1720

1 2 0 R H

1721

1 2 0 R H

1722

1 2 0 R H

1723

1 2 0 R H

1724

1 2 0 R H

1725

1 2 0 R H

1726

1 2 0 R H

1727

1 2 0 R H

TABLE 1.158 Compd. No.

k m n chirality R³

1728

1 2 0 R H

1729

1 2 0 R H

1730

1 2 0 R H

1731

1 2 0 R H

1732

1 2 0 R H

1733

1 2 0 R H

1734

1 2 0 R H

1735

1 2 0 R H

1736

1 2 0 R H

1737

1 2 0 R H

1738

1 2 0 R H

TABLE 1.159 Compd. No.

k m n chirality R³

1739

1 2 0 R H

1740

1 2 0 R H

1741

1 2 0 R H

1742

1 2 0 R H

1743

1 2 0 R H

1744

1 2 0 R H

1745

1 2 0 R H

1746

1 2 0 R H

1747

1 2 0 R H

1748

1 2 0 R H

1749

1 2 0 R H

TABLE 1.160 Compd No.

k m n chirality R³

1750

1 2 0 R H

1751

1 2 0 R H

1752

1 2 0 R H

1753

1 2 0 R H

1754

1 2 0 R H

1755

1 2 0 R H

1756

1 2 0 R H

1757

1 2 0 R H

1758

1 2 0 R H

1759

1 2 0 R H

1760

1 2 0 R H

TABLE 1.161 Compd No.

k m n chirality R³

1761

1 2 0 R H

1762

1 2 0 R H

1763

2 2 0 — H

1764

2 2 0 — H

1765

2 2 0 — H

1766

2 2 0 — H

1767

1 3 1 — H

1768

1 3 1 — H

1769

1 2 0 R H

1770

1 2 0 R H

1771

1 2 0 R H

TABLE 1.162 Compd No.

k m n chira- lity R³

1772

1 2 0 R H

1773

1 2 0 R H

1774

1 2 0 R H

1775

1 2 0 R H

1776

1 2 0 R H

1777

2 2 1 — H

1778

2 2 1 — H

1779

2 2 1 — H

1780

2 2 1 — H

1781

2 2 1 — H

1782

2 2 1 — H

TABLE 1.163 Compd No.

k m n chirality R³

1783

2 2 1 — H

1784

2 2 1 — H

1785

2 2 1 — H

1786

2 2 1 — H

1787

1 2 0 R H

1788

2 2 1 — H

1789

2 2 1 — H

1790

1 2 0 S H

1791

1 2 0 S H

1792

2 2 1 — H

1793

2 2 1 — H

TABLE 1.164 Compd No.

k m n chirality R³

1794

2 2 1 — H

1795

2 2 1 — H

1796

2 2 1 — H

1797

2 2 1 — H

1798

2 2 1 — H

1799

2 2 1 — H

1800

2 2 1 — H

1801

2 2 1 — H

1802

1 2 0 R H

1803

1 2 0 R H

1804

2 2 1 — H

TABLE 1.165 Compd No.

k m n chirality R³

1805

1 2 0 R H

1806

1 2 0 R H

1807

1 2 0 R H

1808

1 2 0 R H

1809

1 2 0 R H

1810

1 2 0 R H

1811

1 2 0 R H

1812

1 2 0 R H

1813

1 2 0 R H

1814

1 2 0 R H

1815

1 2 0 R H

TABLE 1.166 Compd No.

k m n chirality R³

1816

1 2 0 R H

1817

1 2 0 R H

1818

1 2 0 R H

1819

1 2 0 R H

1820

1 2 0 R H

1821

1 2 0 R H

1822

1 2 0 R H

1823

1 2 0 R H

1824

1 2 0 R H

1825

1 2 0 R H

1826

1 2 0 R H

TABLE 1.167 Compd No.

k m n chirality R³

1827

1 2 0 R H

1828

1 2 0 R H

1829

1 2 0 R H

1830

1 2 0 R H

1831

1 2 0 R H

1832

1 2 0 R H

1833

1 2 0 R H

1834

1 2 0 R H

1835

1 2 0 R H

1836

1 2 0 R H

1837

1 2 0 R H

TABLE 1.168 Compd No.

k m n chirality R³

1838

1 2 0 R H

1839

1 2 0 R H

1840

1 2 0 R H

1841

1 2 0 R H

1842

1 2 0 R H

1843

1 2 0 R H

1844

1 2 0 R H

1845

1 2 0 R H

1846

1 2 0 R H

1847

1 2 0 R H

1848

1 2 0 R H

TABLE 1.169 Compd No.

k m n chirality R³

1849

1 2 0 R H

1850

1 2 0 R H

1851

1 2 0 R H

1852

1 2 0 R H

1853

1 2 0 R H

1854

1 2 0 R H

1855

1 2 0 R H

1856

1 2 0 R H

1857

1 2 0 R H

1858

1 2 0 R H

1859

1 2 0 R H

TABLE 1.170 Compd. No.

k m n chirality R³

1860

1 2 0 R H

1861

1 2 0 R H

1862

1 2 0 R H

1863

1 2 0 R H

1864

1 2 0 R H

1865

1 2 0 R H

1866

1 2 0 R H

1867

1 2 0 R H

1868

1 2 0 R H

1869

1 2 0 R H

1870

1 2 0 R H

TABLE 1.171 Compd. No.

k m n chirality R³

1871

1 2 0 R H

1872

1 2 0 R H

1873

1 2 0 R H

1874

1 2 0 R H

1875

1 2 0 R H

1876

1 2 0 R H

1877

1 2 0 R H

1878

1 2 0 R H

1879

1 2 0 R H

1880

1 2 0 R H

1881

1 2 0 R H

TABLE 1.172 Compd. No.

k m n chirality R³

1882

1 2 0 R H

1883

1 2 0 R H

1884

1 2 0 R H

1885

1 2 0 R H

1886

1 2 0 R H

1887

1 2 0 R H

1888

1 2 0 R H

1889

1 2 0 R H

1890

1 2 0 R H

1891

1 2 0 R H

1892

1 2 0 R H

TABLE 1.173 Compd. No.

k m n chirality R³

1893

1 2 0 R H

1894

1 2 0 R H

1895

1 2 0 R H

1896

1 2 0 R H

1897

1 2 0 R H

1898

1 2 0 R H

1899

1 2 0 R H

1900

1 2 0 R H

1901

1 2 0 R H

1902

1 2 0 R H

1903

2 2 1 — H

TABLE 1.174 Compd. No.

k m n chirality R³

1904

2 2 1 — H

1905

1 2 0 R H

1906

1 2 0 R H

1907

1 2 0 R H

1908

1 2 0 R H

1909

1 2 0 R H

1910

2 2 1 — H

1911

2 2 1 — H

1912

2 2 1 — H

1913

2 2 1 — H

1914

2 2 1 — H

TABLE 1.175 Compd. No.

k m n chirality R³

1915

1 2 0 R H

1916

1 2 0 R H

1917

2 2 1 — H

1918

2 2 1 — H

1919

2 2 1 — H

1920

2 2 1 — H

1921

1 2 0 R H

1922

2 2 1 — H

1923

2 2 1 — H

1924

2 2 1 — H

1925

2 2 1 — H

TABLE 1.176 Compd. No.

k m n chirality R³

1926

2 2 1 — H

1927

2 2 1 — H

1928

2 2 1 — H

1929

2 2 1 — H

1930

2 2 1 — H

1931

2 2 1 — H

1932

2 2 1 — H

1933

2 2 1 — H

1934

2 2 1 — H

1935

2 2 1 — H

1936

2 2 1 — H

TABLE 1.177 Compd. No.

k m n chirality R³

1937

2 2 1 — H

1938

2 2 1 — H

1939

2 2 1 — H

1940

2 2 1 — H

1941

2 2 1 — H

1942

2 2 1 — H

1943

2 2 1 — H

1944

2 2 1 — H

1945

2 2 1 — H

1946

2 2 1 — H

1947

2 2 1 — H

TABLE 1.178 Compd. No.

k m n chirality R³

1948

2 2 1 — H

1949

2 2 1 — H

1950

2 2 1 — H

1951

2 2 1 — H

1952

2 2 1 — H

1953

2 2 1 — H

1954

2 2 1 — H

1955

2 2 1 — H

1956

2 2 1 — H

1957

2 2 1 — H

1958

2 2 1 — H

TABLE 1.179 Compd. No.

k m n chirality R³

1959

2 2 1 — H

1960

2 2 1 — H

1961

2 2 1 — H

1962

2 2 1 — H

1963

2 2 1 — H

1964

2 2 1 — H

1965

2 2 1 — H

1966

2 2 1 — H

1967

2 2 1 — H

1968

2 2 1 — H

1969

2 2 1 — H

TABLE 1.180 Compd. No.

k m n chirality R³

1970

2 2 1 — H

1971

2 2 1 — H

1972

2 2 1 — H

1973

2 2 1 — H

1974

2 2 1 — H

1975

2 2 1 — H

1976

2 2 1 — H

1977

2 2 1 — H

1978

2 2 1 — H

1979

2 2 1 — H

1980

2 2 1 — H

TABLE 1.181 Compd. No.

k m n chirality R³

1981

2 2 1 — H

1982

2 2 1 — H

1983

2 2 1 — H

1984

2 2 1 — H

1985

2 2 1 — H

1986

2 2 1 — H

1987

2 2 1 — H

1988

2 2 1 — H

1989

2 2 1 — H

1990

2 2 1 — H

1991

2 2 1 — H

TABLE 1.182 Compd. No.

k m n chirality R³

1992

2 2 1 — H

1993

2 2 1 — H

1994

2 2 1 — H

1995

2 2 1 — H

1996

2 2 1 — H

1997

2 2 1 — H

1998

2 2 1 — H

1999

2 2 1 — H

2000

2 2 1 — H

2001

2 2 1 — H

2002

2 2 1 — H

TABLE 1.183 Compd. No.

k m n chirality R³

2003

2 2 1 — H

2004

2 2 1 — H

2005

2 2 1 — H

2006

2 2 1 — H

2007

2 2 1 — H

2008

2 2 1 — H

2009

2 2 1 — H

2010

2 2 1 — H

2011

2 2 1 — H

2012

2 2 1 — H

2013

2 2 1 — H

TABLE 1.184 Compd. No.

k m n chirality R³

2014

2 2 1 — H

2015

2 2 1 — H

2016

2 2 1 — H

2017

2 2 1 — H

2018

2 2 1 — H

2019

2 2 1 — H

2020

2 2 1 — H

2021

2 2 1 — H

2022

2 2 1 — H

2023

2 2 1 — H

2024

2 2 1 — H

TABLE 1.185 Compd. No.

k m n chirality R³

2025

2 2 1 — H

2026

2 2 1 — H

2027

2 2 1 — H

2028

2 2 1 — H

2029

2 2 1 — H

2030

2 2 1 — H

2031

2 2 1 — H

2032

2 2 1 — H

2033

2 2 1 — H

2034

2 2 1 — H

2035

2 2 1 — H

TABLE 1.186 Compd. No.

k m n chirality R³

2036

2 2 1 — H

2037

2 2 1 — H

2038

2 2 1 — H

2039

2 2 1 — H

2040

1 2 0 R H

2041

1 2 0 R H

2042

1 2 0 R H

2043

1 2 0 R H

2044

1 2 0 R H

2045

1 2 0 R H

2046

1 2 0 R H

TABLE 1.187 Compd. No.

k m n chirality R³

2047

1 2 0 R H

2048

1 2 0 R H

2049

1 2 0 R H

2050

1 2 0 R H

2051

1 2 0 R H

2052

2 2 1 — H

2053

2 2 1 — H

2054

2 2 1 — H

2055

2 2 1 — H

2056

2 2 1 — H

2057

2 2 1 — H

TABLE 1.188 Compd. No.

k m n chirality R³

2058

2 2 1 — H

2059

2 2 1 — H

2060

2 2 1 — H

2061

2 2 1 — H

2062

2 2 1 — H

2063

2 2 1 — H

2064

2 2 1 — H

2065

2 2 1 — H

2066

2 2 1 — H

2067

2 2 1 — H

2068

2 2 1 — H

TABLE 1.189 Compd. No.

k m n chirality R³

2069

2 2 1 — H

2070

2 2 1 — H

2071

2 2 1 — H

2072

2 2 1 — H

2073

2 2 1 — H

2074

2 2 1 — H

2075

2 2 1 — H

2076

2 2 1 — H

2077

2 2 1 — H

2078

2 2 1 — H

2079

2 2 1 — H

TABLE 1.190 Compd. No.

k m n chirality R³

2080

2 2 1 — H

2081

2 2 1 — H

2082

2 2 1 — H

2083

1 2 0 R H

2084

1 2 0 R H

2085

1 2 0 R H

2086

1 2 0 R H

2087

1 2 0 R H

2088

1 2 0 R H

2089

1 2 0 R H

2090

1 2 0 R H

TABLE 1.191 Compd. No.

k m n chirality R³

2091

2 2 1 — H

2092

2 2 1 — H

2093

2 2 1 — H

2094

2 2 1 — H

2095

2 2 1 — H

2096

2 2 1 — H

2097

2 2 1 — H

2098

2 2 1 — H

2099

2 2 1 — H

2100

2 2 1 — H

2101

2 2 1 — H

TABLE 1.192 Compd. No.

k m n chirality R³

2102

2 2 1 — H

2103

2 2 1 — H

2104

2 2 1 — H

2105

2 2 1 — H

2106

2 2 1 — H

2107

2 2 1 — H

2108

2 2 1 — H

2109

2 2 1 — H

2110

2 2 1 — H

2111

2 2 1 — H

2112

2 2 1 — H

TABLE 1.193 Compd. No.

k m n chirality R³

2113

2 2 1 — H

2114

2 2 1 — H

2115

2 2 1 — H

2116

2 2 1 — H

2117

2 2 1 — H

2118

1 2 0 R H

2119

1 2 0 R H

2120

1 2 0 R H

2121

1 2 0 R H

2122

1 2 0 R H

2123

1 2 0 R H

TABLE 1.194 Compd. No.

k m n chirality R³

2124

1 2 0 R H

2125

1 2 0 R H

2126

1 2 0 R H

2127

1 2 0 R H

2128

1 2 0 R H

2129

1 2 0 R H

2130

2 2 1 — H

2131

2 2 1 — H

2132

1 2 0 R H

2133

1 2 0 R H

2134

1 2 0 R H

TABLE 1.195 Compd. No.

k m n chirality R³

2135

1 2 0 R H

2136

1 2 0 R H

2137

1 2 0 R H

2138

1 2 0 R H

2139

1 2 0 R H

2140

2 2 1 — H

2141

2 2 1 — H

2142

2 2 1 — H

2143

2 2 1 — H

2144

2 2 1 — H

2145

2 2 1 — H

TABLE 1.196 Compd. No.

k m n chirality R³

2146

2 2 1 — H

2147

2 2 1 — H

2148

2 2 1 — H

2149

1 2 0 R H

2150

1 2 0 R H

2151

1 2 0 R H

2152

1 2 0 R H

2153

1 2 0 R H

2154

2 2 1 — H

2155

2 2 1 — H

2156

2 2 1 — H

TABLE 1.197 Compd. No.

k m n chirality R³

2157

1 2 0 R H

2158

1 2 0 R H

2159

2 2 1 — H

2160

2 2 1 — H

2161

2 2 1 — H

2162

2 2 1 — H

2163

2 2 1 — H

2164

1 2 0 R H

2165

1 2 0 R H

2166

1 2 0 R H

2167

1 2 0 R H

TABLE 1.198 Compd. No.

k m n chirality R³

2168

1 2 0 R H

2169

1 2 0 R H

2170

1 2 0 R H

2171

1 2 0 R H

2172

1 2 0 R H

2173

1 2 0 R H

2174

1 2 0 R H

2175

1 2 0 R H

2176

1 2 0 R H

2177

1 2 0 R H

2178

1 2 0 R H

TABLE 1.199 Compd. No.

k m n chirality R³

2179

1 2 0 R H

2180

1 2 0 R H

2181

1 2 0 R H

2182

1 2 0 R H

2183

1 2 0 R H

2184

2 2 1 — H

2185

2 2 1 — H

2186

2 2 1 — H

2187

1 2 0 R H

2188

2 2 1 — H

2189

1 2 0 R H

TABLE 1.200 Compd. No.

k m n chirality R³

2190

2 2 1 — H

2191

2 2 1 — H

2192

2 2 1 — H

2193

2 2 1 — H

2194

2 2 1 — H

2195

2 2 1 — H

2196

1 2 0 R H

2197

1 2 0 R H

2198

1 2 0 R H

2199

2 2 1 — H

2200

2 2 1 — H

TABLE 1.201 Compd. No.

k m n chirality R³

2201

2 2 1 — H

2202

1 2 0 R H

2203

2 2 1 — H

2204

2 2 1 — H

2205

2 2 1 — H

2206

2 2 1 — H

2207

2 2 1 — H

2208

2 2 1 — H

2209

2 2 1 — H

The present invention can also use acid addition salt of the cyclic amine compound where such acids include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like, as well as organic acids such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and the like.

Furthermore, the present invention can also use a C₁-C₆ alkyl addition salt of the cyclic amine compound, such as 1-(4-chlorobenzyl)-1-methyl-4-[(N-(3-trifluoromethylbenzoyl)glycyl)aminomethyl]piperidinium iodide, where such alkyl include, for example, a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 1-ethylbutyl, and the like, suitably specifically including, a methyl and ethyl group. As preferred specific examples for counter anion of the ammonium cation, a halide anion such as fluoride, chloride, bromide or iodide can be listed.

The present invention may use racemates and all possible optically active forms of the compound represented by the above formula (I).

Compound represented by the above general formula (I) can be synthesized by any of the general preparations given below.

(Preparation 1)

A preparation which call for treating one equivalent of a compound represented by the formula (II) below:

{where R¹, R², R³, j, k, m, and n are the same as defined respectively in the above formula (I)} with 0.1-10 equivalents of a carboxylic acid represented by the formula (III) below:

{where R⁴, R⁵, R⁶, G, p, and q are the same as defined respectively in the above formula (I)}, or its reactive derivative, either in the absence or presence of solvent.

The reactive derivative for the carboxylic acid in the above formula (III) include highly reactive carboxylic acid derivatives, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides.

Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent such as molecular sieve, coupling reagent such as dicyclohexylcarbodiimide (DCC), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI or WSC), carbonyldiimidazole (CDI), N-hydroxysuccinimide (HOSu), N-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP®), 2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornene-2,3-dicarboxyimido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), bromotris(pyrrolidino)phosphonium hexafluorophos-phate (PyBroP®), and the like, or base including inorganic salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and the like, amines such as triethylamine, diisopropylethylamine, and pyridine, and the like, or polymer supported bases such as (piperidinomethyl)polystyrene, (morpholinomethyl)polystyrene, (diethylaminomethyl)polystyrene, poly(4-vinylpyridine), and the like.

(Preparation 2)

A preparation which calls for treating 1 equivalent of an alkylating reagent given by the formula (IV) below:

{where R¹, R², and j are the same as defined respectively in the above formula (I)}; X represents a halogen atom, alkylsulfonyloxy group, or arylsulfonyloxy group}, with 0.1-10 equivalents of a compound represented by the formula (V) below:

{where R³, R⁴, R⁵, R⁶, G, k, m, n, p, and q are the same as defined respectively in the above formula (I)} either in the absence or presence of solvent.

Such reactions can be more smoothly run if a base similar to that used in the above preparation 1 is present. In addition, the reactions in these preparations can also be promoted by iodide such as potassium iodide, sodium iodide, and the like.

In the above formulas (IV), X represents a halogen atom, alkylsulfonyloxy group, arylsulfonyloxy group. Such halogen atoms include preferably chlorine, bromine, and iodine atoms. Suitable specific examples for the alkylsulfonyloxy groups include methylsulfonyloxy, trifluoromethylsulfonyloxy group, and the like. A preferred specific example for the arylsulfonyloxy group includes a tosyloxy group.

(Preparation 3)

A preparation which calls for treating 1 equivalent of an aldehyde represented by the formula (VI) below:

{where R¹ and R² are the same as defined respectively in the above formula (I); j′ represents 1 or 2} or the formula (VII) below:

R¹—CHO  (VII)

{where R¹ is the same as defined in the above formula (I); j represents 0}, with 0.1-10 equivalents of a compound represented by the formula (V) either in the absence or presence of solvent under reductive conditions.

Such reactions are in general called reductive amination reactions and such reductive conditions may be generated by catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, or the like, using complex hydrides, such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.

(Preparation 4)

A preparation which call for treating one equivalent of a compound represented by the formula (VIII) below:

{where R¹, R², R³, R⁴, R⁵, R⁶, j, k, m, n, p and q are the same as defined respectively in the above formula (I)} with 0.1-10 equivalents of a carboxylic acid or sulfonic acid represented by the formula (IX) below:

HO—A—R⁶  (IX)

{where R⁶ is the same as defined in the above formulas (I); “A” represents a carbonyl group or sulfonyl group}, or its reactive derivative, either in the absence or presence of solvent.

The reactive derivative for the carboxylic acid or sulfonic acid in the above formula (IX) include highly reactive carboxylic acid or sulfonic acid derivative, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides.

Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent, coupling reagent, or base which are similar to those used in the above preparation 1.

(Preparation 5)

A preparation which calls for treating 1 equivalent of a compound represented by the above formula (VIII) with 0.1-10 equivalents of a isocyanate or isothiocyanate represented by the formula (X) below:

Z═C═N—R⁶  (X)

{where R⁶ is the same as defined in the above formulas (I)}; Z represents a oxygen atom or sulfur atom}, either in the absence or presence of solvent.

(Preparation 6)

A preparation which calls for treating 1 equivalent of a compound represented by the formula (XI) below:

{where R¹, R², R³, R⁴, R⁵, j, k, m, n, p and q are the same as defined respectively in the above formula (I)}; “A” represents a carbonyl group or sulfonyl group} with 0.1-10 equivalents of an amine represented by the formula (XII) below:

R⁶—NH₂  (XII)

{where R⁶ is the same as defined in the above formula (I)}, either in the absence or the presence of solvent.

Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent, coupling reagent, or base which are similar to those used in the above preparation 1.

If the substrates submitted to each of the above preparations contains a substituent which reacts under each reaction condition or is thought to adversely affect the reaction in general in synthetic organic chemistry, that functional group can be protected by a known suitable protecting group followed by the reaction of the above preparations and deprotection using a known procedure to obtain the desired compound.

Furthermore, a compound of the present invention can be prepared by the further conversion of the substituent (s) of the compound, prepared with the above preparations 1-6, using known reactions which are usually used in synthetic organic chemistry, such as alkylation, acylation, reduction, and so on.

Each of the above preparations may use solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, and the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, and the like, esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like, alcohols such as methanol, ethanol, isopropyl alcohol, and the like.

The reaction temperature in either of the preparations should be in the range of −78° C.−+150° C., preferably 0° C.−100° C. After completion of the reaction, the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired cyclic amine compound represented by the above formula (I). These can be converted into pharmaceutically acceptable acid addition salt or C₁-C₆ alkyl addition salt by the usual method.

Potential Industrial Utilities

The chemokine receptor antagonist, which contain the cyclic amine compound, its pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable C₁-C₆ alkyl addition salt of this invention, which inhibits chemokines such as MIP-1α and/or MCP-1 and the like from action on target cells, are useful as therapeutic agents and/or preventive preparation for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, and the like, in which tissue infiltration of blood monocytes, lymphocytes, and the like plays a major role in the initiation, progression, and maintenance of the disease.

EXAMPLES

The present invention is now specifically described by the following examples. However, the present invention is not limited to these compounds described in these examples. Compound numbers in these examples represent numbers attached to these compounds listed as suitable specific examples in Tables 1.1-1.201.

Reference Example 1 Preparation of 3-Amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride

4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and ²Pr₂NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH₃CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): ¹H NMR (CDCl₃, 300 MHz) δ 1.37 (s, 9 H), 1.5-1.7 (br, 1 H), 2.1-2.4 (m, 2 H), 2.5-2.7 (m, 2 H), 2.83 (br, 1 H), 3.57 (s, 2 H), 4.1-4.3 (br, 1 H), 4.9-5.1 (br, 1 H), 7.15-7.35 (br, 4 H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M⁺+H, C₁₆H₂₄ClN₂O₂).

A solution of 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol) in CH₃OH (80 mL) was treated with 1 N HCl-Et₂O (100 mL) and was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford a solid which was purified by recrystallization (1:2 CH₃OH—CH₃CN, 150 mL) to give 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride as a white powder (4.939 g, 84.9%): ¹H NMR (d₆-DMSO, 300 MHz) δ 3.15 (br, 1 H), 3.3-3.75 (br-m, 4 H), 3.9 (br, 1 H), 4.05 (br, 1 H), 4.44 (br, 1 H), 4.54 (br, 1 H), 7.5-7.7 (m, 4 H), 8.45 (br, 1 H), 8.60 (br, 1 H); The purity was determined by RPLC/MS (>99%); ESI/MS m/e 211.0 (M⁺+H, C₁₁H₁₆ClN₂).

Optically active (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydro-chloride and (S)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride were also prepared pursuant to the above method using the corresponding reactant respectively. The products showed the same ¹H NMR with that of the racemate.

Example 1 Preparation of 3-(N-Benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1)

N-Benzoylglycine (9.9 mg, 0.055 mmol), 3-ethyl-1-{3(dimethylaminopropyl}carbodiimide hydrochloride (EDCI) (10.5 mg) and 1-hydroxybenzotriazole hydrate (HOBt) (7.4 mg) were added to a solution of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and Et₃N (15.2 mg) in CHCl₃ (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to afford 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 1) as a pale yellow oil (17.7 mg, 95%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 372.0 (M⁺+H, C₂₀H₂₂ClN₃O₂).

Examples 2-32

The compounds of this invention were synthesized pursuant to methods of Example 1 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 2.

TABLE 2 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 2  2 C21 H24 Cl N3 O2 386 16.4 85 Example 3  3 C19 H21 Cl N4 O2 373 18.7 100  Example 4  4 C21 H21 Cl F3 N3 O2 440 57.2 69 Example 5  82 C22 H23 Cl F3 N3 O2 454 5.6 11 Example 6  85 C21 H24 Cl N3 O2 386 22.6 59 Example 7  86 C21 H23 Cl N4 O4 431 21.2 98 Example 8 214 C22 H25 Cl N2 O2 385 23.9 62 Example 9 215 C23 H27 Cl N2 O3 415 17.4 84 Example 10 216 C20 H23 Cl N2 O2 S 391 21.6 quant Example 11 217 C23 H27 Cl N2 O4 431 15.3 66 Example 12 218 C23 H27 Cl N2 O2 399 12.8 64 Example 13 219 C22 H24 Cl F N2 O3 419 18.1 86 Example 14 220 C22 H25 Cl N2 O2 385 16.4 85 Example 15 221 C21 H23 Cl N2 O2 371 14.9 80 Example 16 222 C21 H22 Cl2 N2 O2 405 13.3 65 Example 17 223 C25 H31 Cl N2 O3 443 18.4* 63 Example 18 224 C20 H23 Cl N2 O3 S 407 11.2 28 Example 19 225 C22 H26 Cl N3 O2 400 22.7 quant Example 20 226 C23 H28 Cl N3 O3 430 21.0 98 Example 21 227 C22 H25 Cl2 N3 O2 434 21.9 100  Example 22 228 C23 H28 Cl N3 O3 430 20.8 97 Example 23 229 C25 H32 Cl N3 O2 462 25.4 quant Example 24 230 C26 H31 Cl F N3 O2 472 26.0 quant Example 25 231 C24 H28 Cl N3 O3 442 30.3* quant Example 26 232 C22 H32 Cl N3 O2 406 3.9 19 Example 27 233 C23 H28 Cl N3 O2 414 8.5 41 Example 28 234 C22 H27 Cl N4 O2 415 7.3 35 Example 29 235 C24 H29 Cl2 N3 O2 462 9.0 39 Example 30 236 C25 H29 Cl N4 O3 S 501 17.4 69 Example 31 237 C21 H24 Cl N3 O3 402 14.2 71 Example 32 238 C21 H23 Cl2 N3 O3 436 23.4 quant *Yield of TFA salt.

Reference Example 2 Preparation of (R)-3-{N-(tert-Butoxycarbonyl)glycyl}amino-1-(4-chlorobenzyl)pyrrolidine

A mixture of (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (4.54 g, 16.0 mmol), 2 N NaOH solution (80 mL), and ethyl acetate (80 mL) was shaken, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (80 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give free (R)-3 amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 99%).

A solution of (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 16 mmol) in CH₂Cl₂ (80 mL) was treated with Et₃N (2.5 mL, 17.6 mmol), N-tert-butoxycarbonylglycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (2.16 g, 16 mmol). After the reaction mixture was, stirred at 25° C. for 16 h, 2 N NaOH solution (80 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, ethyl acetate) afforded the desired (R)-3-(N-(tertbutoxycarbonyl)glycyl)amino-1-(4-chlorobenzyl)pyrrolidine (5.40 g, 92%).

Reference Example 3 Preparation of (A)-1-(4-Chlorobenzyl)-3(glycylamino)pyrrolidine.

To a solution of (R)-3-{N-(tert-butoxycarbonyl)glycyl}amino-1-(4-chlorobenzyl)pyrrolidine (5.39 g, 14.7 mmol) in methanol (60 mL) was added 4 N HCl in dioxane (38 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N NaOH solution (80 mL) was added. The mixture was extracted with dichloromethane (80 mL×3), and the combined extracts were dried over sodium sulfate and concentrated. Column chromatography (SiO₂, AcOEt/EtOH/Et₃N=90/5/5) gave (R)-3-(glycyl)amino-1-(4-chlorobenzyl)pyrrolidine (3.374 g, 86%): ¹H NMR (CDCl₃, 270 MHz) δ 1.77 (dd, J=1.3 and 6.9 Hz, 1 H), 2.20-3.39 (m, 2 H), 2.53 (dd, J=3.3H), 2.62 (dd, J=6.6 and 9.6 Hz, 1 H), 2.78-2.87 (m, 1 H), 3.31 (s, 2 H), 3.57 (s, 2 H), 4.38-4.53 (br, 1 H), 7.18-7.32 (m, 4 H), 7.39 (br. s, 1 H).

Other 3-acylamino-1-(4-chlorobenzyl)pyrrolidines were also synthesized pursuant to methods of Reference Example 2 and 3 using the corresponding reactants respectively.

(s)-1-(4-Chlorobenzyl)-3-(glycylamino)pyrrolidine: 3.45 g, 79% (2 steps).

(R)-3-(β-Alanylamino)-1-(4-chlorobenzyl)pyrrolidine: 3.79 g, 85% (2 steps).

(S)-3-(β-Alanylamino-)-1-(4-chlorobenzyl)pyrrolidine: 3.72 g, 86% (2 steps).

(R)-3-{(S)-Alanylamino}-1-(4-chlorobenzyl)pyrrolidine: 368 mg, 65% (2 steps).

(R)-3-{(R)-Alanylamino}-1-(4-chlorobenzyl)pyrrolidine: 425 mg, 75% (2 steps).

(R)-3-{(2 S)-2-Amino-3-thienylpropanoyl}amino-1-(4-chlorobenzyl)pyrrolidine: 566 mg, 78% (2 steps).

(R)-3-{(2 R)-2-Amino-3-thienylpropanoyl}amino-1-(4-chlorobenzyl)pyrrolidine: 585 mg, 81% (2 steps).

(R)-3-(2-Amino-2-methylpropanoyl)amino-1-(4-chlorobenzyl)pyrrolidine: 404 mg, 66% (2 steps).

(R)-3-{(2 S)-2-Amino-4-(methylsulfonyl)butanoyl}amino-1-(4-chlorobenzyl)pyrrolidine: 535 mg, 72% (2 steps).

Furthermore (R)-3-(glycylamino)-1-(4-methylbenzyl)pyrrolidine, (R)-1-(4-bromobenzyl)-3-(glycylamino)pyrrolidine, (R)-1-(2,4-dimethylbenzyl)-3(glycylamino)pyrrolidine, and (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3(glycylamino)pyrrolidine were also synthesized pursuant to methods of Reference Example 1, 2 and 3 using the corresponding reactants respectively.

(R)-3-(Glycylamino)-1-(4-methylbenzyl)pyrrolidine: 4.65 g, 62% yield from 3-((tert-butoxycarbonyl)amino)pyrrolidine.

(R)-1-(4-Bromobenzyl)-3-(glycylamino)pyrrolidine: 2.55 g, 68% yield from (R)-3-amino-1-(4-bromobenzyl)pyrrolidine; ¹H NMR (CDCl₃, 270 MHz) δ 1.37-1.78 (m, 3 H), 2.23-2.39 (m, 2 H), 2.50-2.67 (m, 2 H), 2.80-2.89 (m, 1 H), 3.32 (s, 2 H), 3.58 (s, 2 H), 4.39-4.55 (m, 1 H), 7.21 (d, J=6.5 Hz, 2 H), 7.45 (d, J=6.5 Hz, 2 H).

(R)-1-(2,4-Dimethylbenzyl)-3-(glycylamino)pyrrolidine: 1.56 g, 58% yield from 3-{(tert-butoxycarbonyl)amino}pyrrolidine; ¹H NMR (CDCl₃, 270 MHz) δ 1.55-1.78 (m, 3 H), 2.30(s, 3 H), 2.23-2.31 (m, 2 H), 2.33(s,3 H), 2.51-2.63 (m, 2 H), 2.78-2.87 (m, 1 H), 3.30 (s, 2 H), 3.55 (s, 2 H), 4.38-4.60 (m, 1 H), 6.95 (d, J=7.6 Hz, 1 H), 6.97 (s, 1 H), 7.13 (d, J=7.6 Hz, 1 H), 7.43 (br-s, 1 H).

(R)-1-(3,5-Dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine: 3.14 g, 45% yield from 3-{(tert-butoxycarbonyl)amino}pyrrolidine.

Example 33 Preparation of (S)-3-[N-{3,5-Bis (trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (Compound No. 5)

A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) in chloroform. (0.4 mL) was added to a solution of (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give (S)-3-[N-{3,5-bis(trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 5) (14.4 mg, 57%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 508.0 (M⁺+H, C₂₂H₂₀ClF₆N₃O₂).

Examples 34-239

The compounds of this invention were synthesized pursuant to methods of Example 33 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 3.

TABLE 3 Compound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 34  5 C₂₂H₂₃ClF₆N₃O₂ 508.0 14.4 57 Example 35  6 C₂₁H₂₁ClF₅N₃O₂ 440.0 17.0 77 Example 36  7 C₂₆H₂₁BrClN₃O₂ 450.0 17.7 79 Example 37  8 C₂₀H₂₁ClFN₃O₂ 390.0 12.7 65 Example 38  9 C₂₀H₂₀Cl₃N₃O₂ 440.0 39.0 quant Example 39  10 C₂₁H₂₄ClN₃O₃ 402.5 23.5 quant Example 40  11 C₂₂H₂₆ClN₃O₄ 432.5 22.4 quant Example 41  12 C₂₂H₂₆ClN₃O₄ 432.5 15.9 74 Example 42  13 C₂₁H₂₁ClF₃N₃O₂ 440.0 13.1 60 Example 43  14 C₂₁H₂₄ClN₃O₂ 386.0 16.4 85 Example 44  15 C₂₀H₂₁Cl₂N₃O₂ 406.0 15.7 77 Example 45  16 C₂₁H₂₄ClN₃O₂ 402.0 28.2 quant Example 46  17 C₂₀H₂₀Cl₃N₃O₂ 442.0 35.6 quant Example 47  18 C₂₁H₂₁ClN₄O₂ 397.5 22.8 quant Example 48  19 C₂₁H₂₂ClN₃O₄ 416.0 16.3 78 Example 49  20 C₂₁H₂₀ClF₄N₃O₂ 458.0 24.9 quant Example 50  21 C₂₁H₂₀ClF₄N₃O₂ 458.0 17.9 78 Example 51  22 C₂₁H₂₀ClF₄N₃O₂ 458.0 9.4 41 Example 52  23 C₂₁H₂₀ClF₄N₃O₂ 458.0 15.4 67 Example 53  24 C₂₁H₂₁ClF₃N₃O₂ 456.0 20.7 91 Example 54  25 C₂₁H₂₀ClF₄N₃O₂ 458.0 18.5 81 Example 55  26 C₂₀H₂₁ClN₄O₄ 417.0 21.9 quant Example 56  27 C₂₀H₂₁ClN₄O₄ 417.0 16.8 81 Example 57  28 C₂₀H₂₁ClN₄O₄ 417.0 6.8 33 Example 58  29 C₂₂H₂₀ClF₆N₃O₂ 508.0 20.8 82 Example 59  30 C₂₁H₂₁ClF₃N₃O₂ 440.0 15.2 69 Example 60  31 C₂₀H₂₁BrClN₃O₂ 450.0 15.6 69 Example 61  32 C₂₀H₂₁ClFN₃O₂ 390.0 11.8 61 Example 62  33 C₂₀H₂₀Cl₃N₃O₂ 440.0 15.8 72 Example 63  34 C₂₁H₂₄ClN₃O₃ 402.5 33.8 quant Example 64  35 C₂₂H₂₆ClN₃O₄ 432.5 56.1 quant Example 65  36 C₂₂H₂₆ClN₃O₄ 432.5 37.6 quant Example 66  37 C₂₁H₂₁ClF₃N₃O₂ 440.0 12.6 57 Example 67  38 C₂₁H₂₄ClN₃O₂ 386.0 12.3 64 Example 68  39 C₂₀H₂₁Cl₂N₃O₂ 406.0 15.9 78 Example 69  40 C₂₁H₂₄ClN₃O₂ 402.0 11.6 58 Example 70  41 C₂₀H₂₀Cl₃N₃O₂ 442.0 17.8 81 Example 71  42 C₂₁H₂₁ClN₄O₂ 397.5 22.4 quant Example 72  43 C₂₁H₂₂ClN₃O₄ 416.0 30.1 quant Example 73  44 C₂₁H₂₀ClF₄N₃O₂ 458.0 13.4 59 Example 74  45 C₂₁H₂₀ClF₄N₃O₂ 458.0 13.2 58 Example 75  46 C₂₁H₂₀ClF₄N₃O₂ 458.0 14.4 63 Example 76  47 C₂₁H₂₁ClF₃N₃O₃ 456.0 16.4 72 Example 77  48 C₂₁H₂₀ClF₄N₃O₂ 458 16.5 72 Example 78  49 C₂₀H₂₁ClN₄O₄ 417.0 12.5 60 Example 79  50 C₂₁H₂₀ClF₄N₃O₂ 458.0 26.3 quant Example 80  51 C₂₀H₂₁BrClN₃O₂ 450.0 8.6 38 Example 81  52 C₂₀H₂₁ClFN₃O₂ 390.5 4.1 21 Example 82  53 C₂₀H₂₁Cl₂N₃O₂ 406.0 5.4 27 Example 83  54 C₂₀H₂₀Cl₃N₃O₂ 440.0 8.8 40 Example 84  55 C₂₀H₂₀BrCl₄N₃O₂ 440.0 7.7 35 Example 85  56 C₂₁H₂₄ClN₃O₂ 386.0 4.8 25 Example 86  57 C₂₂H₂₆ClN₃O₄ 429.5 4.9 23 Example 87  58 C₂₀H₂₁Cl₂N₃O₂ 406.0 4.1 20 Example 88  59 C₂₀H₂₁BrClN₃O₂ 452.0 3.5 16 Example 89  60 C₂₆H₂₆ClN₃O₂ 448.5 7.3 33 Example 90  61 C₂₁H₂₁ClF₃N₃O₂ 440.0 7.1 32 Example 91  62 C₂₁H₂₄ClN₃O₂ 386.0 10.4 54 Example 92  63 C₂₂H₂₆ClN₃O₂ 400.5 6.0 30 Example 93  64 C₂₁H₂₁ClN₄O₂ 397.0 7.0 35 Example 94  65 C₂₄H₂₄ClN₃O₂ 422.0 7.7 36 Example 95  66 C₂₄H₂₄ClN₃O₂ 422.0 6.3 30 Example 96  67 C₂₀H₂₀ClF₂N₃O₂ 408.0 4.7 23 Example 97  68 C₂₀H₂₀ClF₂N₃O₂ 408.0 7.8 38 Example 98  69 C₂₀H₂₀ClF₂N₃O₂ 408.0 7.3 36 Example 99  70 C₂₀H₂₀ClF₂N₃O₂ 408.0 9.1 45 Example 100  71 C₂₂H₂₆ClN₃O₄ 429.0 5.6 26 Example 101  72 C₂₁H₂₁ClF₃N₃O₂ 456.0 6.2 27 Example 102  73 C₂₁H₂₁ClF₃N₃O₂ 456.5 16.8 74 Example 103  74 C₂₂H₂₄ClN₃O₄ 430.0 16.4 76 Example 104  75 C₂₁H₂₀ClF₄N₃O₂ 458.0 16.1 70 Example 105  76 C₂₁H₂₀ClF₄N₃O₂ 458.0 17.0 74 Example 106  77 C₂₀H₁₉ClF₃N₃O₂ 426.0 16.2 76 Example 107  78 C₂₀H₁₉ClF₃N₃O₂ 426.0 18.0 85 Example 108  79 C₂₂H₂₀ClF₆N₃O₂ 508.0 18.8 74 Example 109  80 C₂₂H₂₀ClF₆N₃O₂ 508.0 16.4 65 Example 110  81 C₂₂H₂₆ClN₃O₂ 400.0 13.9 70 Example 111  83 C₂₀H₂₃ClN₄O₄ 417.0 16.0 77 Example 112  84 C₂₀H₂₁ClN₄O₄ 417.0 21.6 quant Example 113  87 C₂₃H₂₂ClF₆N₃O₂ 522.0 17.5 67 Example 114  88 C₂₂H₂₃ClF₃N₃O₂ 454.0 13.9 61 Example 115  89 C₂₁H₂₃BrClN₃O₂ 466.0 15.4 66 Example 116  90 C₂₁H₂₃ClFN₃O₂ 404.0 10.7 53 Example 117  91 C₂₁H₂₂Cl₃N₃O₂ 456.0 13.7 60 Example 118  92 C₂₂H₂₆ClN₃O₃ 416.0 38.4 quant Example 119  93 C₂₃H₂₈ClN₃O₄ 446.0 25.2 quant Example 120  94 C₂₃H₂₈ClN₃O₄ 446.0 16.5 74 Example 121  95 C₂₂H₂₃ClF₃N₃O₂ 454.0 16.3 72 Example 122  96 C₂₂H₂₆ClN₃O₂ 400.5 16.7 84 Example 123  97 C₂₁H₂₃Cl₂N₃O₂ 420.0 11.2 53 Example 124  98 C₂₂H₂₆ClN₃O₂ 416.5 11.8 57 Example 125  99 C₂₁H₂₂Cl₃N₃O₂ 454.0 14.8 65 Example 126 100 C₂₂H₂₃ClN₄O₂ 411.0 9.5 46 Example 127 101 C₂₂H₂₄ClN₃O₄ 430.5 13.2 61 Example 128 102 C₂₂H₂₂ClF₄N₃O₂ 472.0 13.1 56 Example 129 103 C₂₂H₂₂ClF₄N₃O₂ 472.0 36.5 quant Example 130 104 C₂₂H_(22ClF) ₄N₃O₂ 472.0 22.8 97 Example 131 105 C₂₂H₂₂ClF₄N₃O₂ 472.0 20.1 85 Example 132 106 C₂₂H₂₃ClF₃N₃O₃ 470.0 27.4 quant Example 133 107 C₂₂H₂₂ClF₄N₃O₂ 472.0 18.5 78 Example 134 108 C₂₁H₂₃ClN₄O₄ 431.0 11.9 55 Example 135 109 C₂₁H₂₃ClN₄O₄ 431.0 23.9 quant Example 136 110 C₂₁H₂₃ClN₄O₄ 431.0 24.4 quant Example 137 111 C₂₃H₂₃ClF₆N₃O₂ 522.0 9.5 36 Example 138 112 C₂₂H₂₃ClF₃N₃O₂ 454.0 3.9 17 Example 139 113 C₂₁H₂₃BrClN₃O₂ 466.0 7.5 32 Example 140 114 C₂₁H₂₃ClFN₃O₂ 404.0 6.1 30 Example 141 115 C₂₁H₂₂Cl₃N₃O₂ 456.0 6.6 29 Example 142 116 C₂₂H₂₆ClN₃O₃ 416.0 4.8 23 Example 143 117 C₂₃H₂₈ClN₃O₄ 446.0 6.4 29 Example 144 118 C₂₃H₂₈ClN₃O₄ 446.0 24.6 quant Example 145 119 C₂₂H₂₂ClF₃N₃O₂ 454.0 5.2 23 Example 146 120 C₂₂H₂₆ClN₃O₂ 400.5 4.4 22 Example 147 121 C₂₁H₂₃Cl₂N₃O₂ 420.0 7.8 37 Example 148 122 C₂₂H₂₆ClN₃O₂ 416.5 14.1 68 Example 149 123 C₂₁H₂₃Cl₃N₃O₂ 454.0 5.4 24 Example 150 124 C₂₂H₂₃ClN₄O₂ 411.0 34.0 quant Example 151 125 C₂₂H₂₄ClN₃O₄ 430.5 32.0 quant Example 152 126 C₂₂H₂₂ClF₄N₃O₂ 472.0 4.6 19 Example 153 127 C₂₂H₂₂ClF₄N₃O₂ 472.0 10.4 44 Example 154 128 C₂₂H₂₃ClF₄N₃O₂ 472.0 7.3 31 Example 155 129 C₂₂H₂₂ClF₄N₃O₂ 472.0 13.5 57 Example 156 130 C₂₂H₂₃ClF₃N₃O₃ 470.0 15.1 64 Example 157 131 C₂₂H₂₂ClF₄N₃O₂ 472.0 8.6 36 Example 158 132 C₂₁H₂₃ClN₄O₄ 431.0 4.4 20 Example 159 133 C₂₁H₂₃ClN₄O₄ 431.0 32.0 quant Example 160 134 C₂₁H₂₃ClN₄O₄ 431.0 6.9 32 Example 161 135 C₂₁H₂₃BrClN₃O₂ 466.0 7.8 34 Example 162 136 C₂₁H₂₃ClFN₃O₂ 404.0 13.7 68 Example 163 137 C₂₁H₂₃Cl₂N₃O₂ 420.5 14.6 69 Example 164 138 C₂₁H₂₂ClIN₃O₂ 454.0 17.7 78 Example 165 139 C₂₁H₂₂BrCl₄N₃O₂ 454.0 17.2 76 Example 166 140 C₂₂H₂₆ClN₃O₂ 400.0 15.0 75 Example 167 141 C₂₃H₂₈ClN₃O₄ 443.5 13.9 62 Example 168 142 C₂₁H₂₃Cl₂N₃O₂ 420.0 13.7 65 Example 169 143 C₂₁H₂₃BrClN₃O₂ 464.0 16.1 69 Example 170 144 C₂₇H₂₈ClN₃O₂ 462.0 17.6 76 Example 171 145 C₂₂H₂₃ClF₃N₃O₂ 454.0 16.0 71 Example 172 146 C₂₂H₂₆ClN₃O₂ 400.0 14.9 75 Example 173 147 C₂₃H₂₈ClN₃O₂ 414.0 16.2 78 Example 174 148 C₂₂H₂₃ClN₄O₂ 411.0 14.9 73 Example 175 149 C₂₅H₂₆ClN₃O₂ 436.0 17.1 78 Example 176 150 C₂₅H₂₆ClN₃O₂ 436.0 13.1 60 Example 177 151 C₂₁H₂₂ClF₂N₃O₂ 422.0 14.8 70 Example 178 152 C₂₁H₂₃ClF₂N₃O₂ 422.0 15.3 73 Example 179 153 C₂₁H₂₂ClF₂N₃O₂ 422.0 15.3 73 Example 180 154 C₂₁H₂₂ClF₂N₃O₂ 422.0 16.4 78 Example 181 155 C₂₃H₂₈ClN₃O₄ 443.0 16.9 76 Example 182 156 C₂₂H₂₃ClF₃N₃O₂ 470.5 12.6 54 Example 183 157 C₂₂H₂₃ClF₃N₃O₂ 470.0 20.0 85 Example 184 158 C₂₃H₂₆ClN₃O₄ 444.0 17.4 78 Example 185 159 C₂₂H₂₂ClF₄N₃O₂ 472.0 18.4 78 Example 186 160 C₂₂H₂₂ClF₄N₃O₂ 472.0 19.6 83 Example 187 161 C₂₁H₂₁ClF₃N₃O₂ 440.0 17.0 77 Example 188 162 C₂₁H₂₁ClFN₃O₂ 440.0 17.1 78 Example 189 163 C₂₃H₂₂ClF₆N₃O₂ 522.0 20.8 80 Example 190 164 C₂₃H₂₂ClF₆N₃O₂ 522.0 2.7 10 Example 191 165 C₂₃H₂₈ClN₃O₂ 414.0 16.4 79 Example 192 166 C₂₂H₂₃ClF₃N₃O₂ 454.0 8.6 38 Example 193 167 C₂₁H₂₃BrClN₃O₂ 464.0 11.6 50 Example 194 168 C₂₁H₂₃Cl₂N₃O₂ 420.0 11.5 55 Example 195 169 C₂₁H₂₂Cl₃N₃O₂ 454.0 10.0 44 Example 196 170 C₂₂H₂₂ClF₄N₃O₂ 472.0 10.4 44 Example 197 171 C₂₁H₂₃Cl₂N₃O₂ 420.0 8.9 42 Example 198 172 C₂₁H₂₄ClN₃O₂ 386.0 10.3 53 Example 199 173 C₂₁H₂₃ClN₄O₄ 431.0 14.6 68 Example 200 174 C₂₂H₂₃ClF₃N₃O₂ 454.0 10.4 46 Example 201 175 C₂₁H₂₃BrClN₃O₂ 464.0 13.4 58 Example 202 176 C₂₁H₂₃Cl₂N₃O₂ 420.0 12.7 60 Example 203 177 C₂₁H₂₂Cl₃N₃O₂ 454.0 13.2 58 Example 204 178 C₂₂H₂₃ClF₄N₃O₂ 472.0 12.9 55 Example 205 179 C₂₁H₂₃Cl₂N₃O₂ 420.0 13.3 63 Example 206 180 C₂₁H₂₄ClN₃O₂ 386.0 24.2 quant Example 207 181 C₂₁H₂₅ClN₄O₄ 431.0 1.0  1 Example 208 182 C₂₃H₂₅ClF₃N₃O₂ 468.0 15.1 65 Example 209 183 C₂₂H₂₅BrClN₃O₂ 478.0 18.0 75 Example 210 184 C₂₂H₂₅Cl₂N₃O₂ 434.0 16.3 75 Example 211 185 C₂₂H₂₄Cl₃N₃O₂ 468.0 18.6 79 Example 212 186 C₂₃H₂₄ClF₄N₃O₂ 486.0 16.5 68 Example 213 187 C₂₂H₂₅Cl₂N₃O₂ 434.0 14.4 66 Example 214 188 C₂₂H₂₆ClN₃O₂ 400.0 14.0 70 Example 215 189 C₂₂H₂₅ClN₄O₄ 445.0 16.8 76 Example 216 190 C₂₆H₂₅ClF₃N₃O₂S 536.0 17.7 66 Example 217 191 C₂₅H₂₅BrClN₃O₂S 546.0 20.4 75 Example 218 192 C₂₅H₂₅Cl₂N₃O₂S 502.0 16.9 67 Example 219 193 C₂₅H₂₄Cl₃N₃O₂S 536.0 18.3 68 Example 220 194 C₂₆H₂₄ClF₄N₃O₂S 554.0 19.4 70 Example 221 195 C₂₅H₂₅Cl₂N₃O₂S 502.0 19.1 76 Example 222 196 C₂₅H₂₆ClN₃O₂S 468.0 16.0 68 Example 223 197 C₂₅H₂₅ClN₄O₄S 513.0 18.4 72 Example 224 198 C₂₆H₂₅ClF₃N₃O₂S 536.0 13.9 52 Example 225 199 C₂₅H₂₅BrClN₃O₂S 546.0 12.9 47 Example 226 200 C₂₅H₂₅Cl₂N₃O₂S 502.0 15.6 -62 Example 227 201 C₂₅H₂₄Cl₃N₃O₂S 536.0 17.3 64 Example 228 202 C₂₆H₂₄ClF₄N₃O₂S 554.0 15.4 56 Example 229 203 C₂₅H₂₅Cl₂N₃O₂S 502.0 13.5 54 Example 230 204 C₂₅H₂₆ClN₃O₂S 468.0 13.7 59 Example 231 205 C₂₅H₂₅ClN₄O₄S 513.0 13.9 54 Example 232 206 C₂₄H₂₇ClF₃N₃O₄S 546.0 10.0 37 Example 233 207 C₂₃H₂₇BrClN₃O₄S 558.0 17.1 61 Example 234 208 C₂₃H₂₇Cl₂N₃O₄S 512.0 17.0 66 Example 235 209 C₂₃H₂₆Cl₃N₃O₄S 546.0 7.3 27 Example 236 210 C₂₄H₂₆ClF₄N₃O₄S 564.0 19.2 68 Example 237 211 C₂₃H₂₇Cl₂N₃O₄S 512.0 7.9 31 Example 238 212 C₂₃H₂₈ClN₃O₄S 478.0 13.7 57 Example 239 213 C₂₃H₂₇ClN₄O₄S 523.0 5.5 21

Example 240 Preparation of (R)-3-[N-(3-Fluoro-5(trifluoromethyl)benzoyl)glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)pyrrolidine (Compound No. 1191)

A solution of 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a mixture of (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 mL). After the reaction mixture was stirred at room temperature for 2 h, methanol (1.0 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH₃OH (16 mL). Product was eluted off using 2 N NH₃ in CH₃OH (6 mL) and concentrated to afford (R)-3-[N-(3-fluoro-5-(trifluoromethyl)benzoyl)glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)pyrrolidine (Compound No. 1191) (19.5 mg, 88%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 443.2 (M⁺+H, C₂₀H₂₂F₄N₄O₃).

Examples 241-265

The compounds of this invention were synthesized pursuant to methods of Example 240 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 4.

TABLE 4 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 241 1192 C20 H22 F4 N4 O3 443.2 19.2 87 Example 242 1193 C20 H23 F3 N4 O4 441.0 17.5 79 Example 243 1194 C21 H22 F6 N4 O3 493.0 20.4 83 Example 244 1195 C19 H23 Br N4 O3 435.1 16.8 77 Example 245 1196 C19 H23 N5 O5 402.2 16.2 81 Example 246 1197 C20 H22 F4 N4 O3 443.2 17.6 80 Example 247 1198 C19 H23 Cl N4 O3 391.0 16.5 84 Example 248 1199 C20 H26 N4 O3 371.0 16.1 87 Example 249 1200 C19 H22 Cl2 N4 O3 425.0 18.0 85 Example 250 1201 C19 H22 F2 N4 O3 393.0 16.6 85 Example 251 1202 C20 H22 F4 N4 O3 443.2 16.8 76 Example 252 1203 C22 H24 F3 N3 O3 436.2 17.1 79 Example 253 1204 C23 H23 F6 N3 O2 488.2 18.1 74 Example 254 1205 C21 H24 Br N3 O2 430.0 17.5 81 Example 255 1206 C21 H24 N4 O4 397.0 16.2 82 Example 256 1207 C22 H23 F4 N3 O2 438.2 17.5 80 Example 257 1208 C21 H24 Cl N3 O2 386.0 15.8 82 Example 258 1209 C22 H27 N3 O2 366.0 15.7 86 Example 259 1210 C21 H23 Cl2 N3 O2 420.0 17.8 85 Example 260 1211 C21 H23 F2 N3 O2 388.0 16.3 84 Example 261 1212 C22 H23 F4 N3 O2 438.2 17.4 80 Example 262 1213 C24 H24 Cl F6 N3 O2 536.2 24.0 90 Example 263 1214 C23 H24 Cl F4 N3 O3 486.2 22.2 91 Example 264 1215 C22 H24 Cl3 N3 O2 467.9 20.9 89 Example 265 1216 C22 H24 Cl F2 N3 O2 436.0 19.3 89

Example 266 Preparation of (R)-1-(4-Chlorobenzyl)-3-[{N-(4(dimethylamino)benzoyl)glycyl}amino]pyrrolidine (Compound No. 952)

A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (13.8 mg, 0.052 mmol) in CHCl₃ (2 mL) was treated with Et₃N (0.021 mL, 0.15 mmol), 4-(dimethylamino)benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was washed with 2 N aqueous NaOH solution (2 mL×2) and brine (2 mL), and dried by filtration through a PTFE membrane using CH₂Cl₂ (3 mL). Concentration afforded the desired material (compound No. 952) (24.9 mg, quant): The purity was determined by RPLC/MS (91%); ESI/MS m/e 415.0 (M⁺+H, C₂₂H₂₇ClN₄O₂)

Examples 267-347

The compounds of this invention were synthesized pursuant to methods of Example 266 using the corresponding reactant respectively. Solid-phase extraction (Varian™ SCX column) or chromatography (HPLC-C₁₈), if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 5.

TABLE 5 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 267  951 C22 H24 Cl N3 O4 430.0 26.3 quant Example 268  953 C23 H29 Cl N4 O2 429.0 28.8 quant Example 269  954 C21 H25 Cl N4 O2 401.0 27.9 quant Example 270  955 C22 H27 Cl N4 O2 415.0 26.8 quant Example 271  956 C21 H24 Cl N3 O3 402.0 10.3 51 Example 272  957 C20 H22 Cl N3 O3 388.0 1.4  7 Example 273  958 C21 H24 Cl N3 O3 402.5 1.2  6 Example 274  959 C22 H25 Cl N4 O3 429.5 4.7 22 Example 275  960 C23 H27 Cl N4 O3 443.0 10.9 49 Example 276  961 C21 H25 Cl N4 O2 401.0 28.4 quant Example 277  962 C22 H27 Cl N4 O2 415.0 24.9 quant Example 278  963 C21 H24 Cl N3 O3 402.0 4.4 22 Example 279  964 C22 H24 Cl N3 O4 430.0 29.5 quant Example 280  965 C23 H26 Cl N3 O4 444.0 27.2 quant Example 281  966 C22 H24 Cl N3 O3 414.0 27.0 quant Example 282  967 C23 H26 Cl N3 O3 428.0 27.0 quant Example 283  968 C22 H23 Cl N4 O2 411.0 21.4 quant Example 284  969 C23 H25 Cl N4 O2 425.0 27.6 quant Example 285  970 C22 H27 Cl N4 O2 415.0 28.6 quant Example 286  971 C23 H29 Cl N4 O2 429.0 27.9 quant Example 287  972 C20 H23 Cl N4 O2 387.0 26.2 quant Example 288  973 C21 H25 Cl N4 O2 401.0 26.8 quant Example 289  974 C20 H23 Cl N4 O2 387.0 26.6 quant Example 290  975 C21 H25 Cl N4 O2 401.0 28.2 quant Example 291  976 C22 H23 Cl N4 O2 411.0 29.2 quant Example 292  977 C23 H25 Cl N4 O2 425.0 29.5 quant Example 293  978 C20 H21 Cl N6 O2 413.0 2.2 11 Example 294  979 C21 H23 Cl N6 O2 427.0 10.2 48 Example 295  980 C22 H25 Cl N4 O3 429.0 28.8 quant Example 296  981 C23 H27 Cl N4 O3 443.0 11.9 54 Example 297  982 C22 H27 Cl N4 O2 415.0 27.4 quant Example 298  983 C23 H29 Cl N4 O2 429.5 28.1 quant Example 299  984 C21 H24 Cl N3 O3 402.0 27.7 quant Example 300  985 C22 H26 Cl N3 O3 416.0 28.6 quant Example 301 1149 C21 H28 N4 O4 401 15.5* 38 Example 302 1150 C21 H28 N4 O3 385 10.9* 28 Example 303 1151 C21 H25 F3 N4 O3 439 17.3* 39 Example 304 1152 C21 H24 F N5 O3 415 12.7* 30 Example 305 1153 C21 H24 Cl N5 O3 430 17.5* 41 Example 306 1154 C22 H27 N5 O3 410 20.6* 50 Example 307 1155 C19 H23 F3 N4 O4 429 13.8* 32 Example 308 1156 C21 H30 N4 O4 403 17.7* 43 Example 309 1157 C18 H24 N4 O3 S2 409 12.6* 30 Example 310 1158 C19 H23 Cl2 N5 O3 440 16.9* 38 Example 311 1159 C22 H31 N5 O6 462 38.6* 85 Example 312 1160 C20 H26 Br N5 O3 464 20.4 45 Example 313 1289 C20 H27 N5 O4 403 5.8* 14 Example 314 1290 C21 H29 N5 O3 400 6.9* 17 Example 315 1291 C24 H28 N4 O2 405 22.4 68 Example 316 1292 C22 H27 Br N4 O2 461 23.8 15 Example 317 1293 C22 H23 F4 N3 O2 438 20.9 59 Example 318 1294 C22 H23 F4 N3 O2 438 20.8 59 Example 319 1295 C23 H31 N3 O3 398 17.5 54 Example 320 1296 C20 H25 N3 O2 S2 404 18.8 58 Example 321 1297 C21 H24 F3 N3 O3 424 18.1 53 Example 322 1388 C21 H32 N6 O3 417 7.4* 24 Example 323 1389 C19 H22 N6 O4 399 15.2 48 Example 324 1401 C23 H25 Cl N4 O2 425 8.3* 16 Example 325 1402 C24 H32 N4 O5 457 8.3* 15 Example 326 1403 C20 H24 N4 O2 353 14.8 52 Example 327 1404 C20 H24 N4 O2 353 17.0 60 Example 328 1405 C21 H26 N4 O2 S 399 17.3 54 Example 329 1407 C22 H28 N4 O2 S 413 19.1 57 Example 330 1410 C19 H24 N4 O3 357 9.7* 59 Example 331 1769 C22 H26 Cl F3 N4 O5 519 11.6* 20 Example 332 1770 C26 H28 Cl2 N6 O4 559 13.1* 21 Example 333 1771 C26 H37 N5 O4 484 12.7* 23 Example 334 1772 C28 H39 N5 O4 510 5.5*  9 Example 335 1773 C28 H37 N5 O4 509 6.2* 11 Example 336 1774 C28 H34 N6 O6 551 13.6* 22 Example 337 2039 C19 H24 N4 O2 341 5.2* 14 Example 338 2040 C22 H27 N3 O4 398 2.0*  5 Example 339 2041 C23 H29 N3 O3 396 6.2* 15 Example 340 2042 C25 H37 N3 O2 413 2.6*  6 Example 341 2043 C24 H31 N3 O2 394 6.8* 17 Example 342 2044 C25 H28 N4 O4 449 8.7* 16 Example 343 2045 C26 H29 Cl N6 O4 525 11.4* 19 Example 344 2046 C27 H32 N6 O4 505 7.7* 13 Example 345 2047 C28 H32 N4 O4 489 10.0* 18 Example 346 2048 C28 H37 N5 O5 524 3.7*  6 Example 347 2049 C28 H37 N5 O4 509 5.3*  9 *Yield of TFA salt.

Example 348 Preparation of (R)-1-(4-Chlorobenzyl)-3-[{N-(2-amino-5-chlorobenzoyl)glycyl}amino]pyrrolidine (Compound No. 1084)

A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in CHCl₃ (2 mL) was treated with 2-amino-5-chlorobenzoic acid (0.060 mmol) and diisopropylcarbodiimide (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH₃OH (15 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford (R)-1-(4-chlorobenzyl)-3-[N-{2-amino-5-chlorobenzoyl)glycyl}amino]pyrrolidine (Compound No. 1084) (12.7 mg, 60%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 421.0 (M⁺+H, C₂₀H₂₂Cl₂N₄O₂).

Examples 349-361

The compounds of this invention were synthesized pursuant to methods of Example 348 using the corresponding reactant respectively. If the starting amine remained, treatment with isocyanatomethylated polystyrene (50 mg) in CHCl₃ (1 mL) at room temperature, filtration and concentration afforded the desired material. The ESI/MS data and yields are summarized in Table 6.

TABLE 6 Compound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 349 1085 C₂₀H₂₂ClN₅O₄ 432.0 4.1 19 Example 350 1086 C₂₀H₂₃ClN₄O₂ 387.0 7.9 41 Example 351 1087 C₂₂H₂₃ClN₄O₂ 411.0 15.0 73 Example 352 1088 C₁₈H₂₀ClN₃O₃ 362.0 12.9 71 Example 353 1089 C₂₂H₂₂ClFN₄O₂ 429.0 16.0 75 Example 354 1090 C₂₂H₂₆ClN₃O₃ 416.0 15.8 76 Example 355 1091 C₂₁H₂₄Cl₂N₄O₂ 435.0 10.9 50 Example 356 1092 C₂₁H₂₄ClN₅O₄ 446.0 7.9 35 Example 357 1093 C₂₁H₂₅ClN₄O₂ 401.0 9.5 47 Example 358 1094 C₂₃H₂₅ClN₄O₂ 425.0 15.8 74 Example 359 1095 C₁₉H₂₂ClN₃O₃ 376.0 13.5 72 Example 360 1096 C₂₃H₂₄ClFN₄O₂ 443.0 11.8 53 Example 361 1097 C₂₅H₂₈ClN₂O₃ 430.0 15.1 70

Example 362 Preparation of (R)-1-(4-Chlorobenzyl)-3-[{N-(3-bromo-4-methylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1099)

A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in CHCl₃ (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian^(T) SCX column, and washed with CH₃OH/CHCl₃ 1:1 (12 mL) and CH₃OH (12 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford (R)-1-(4-chlorobenzyl)-3-[{N-(3-bromo-4-methylbenzoyl)glycol}amino]pyrrolidine (Compound No. 1098) (11.6 mg, 50%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 466.0 (C₂₁H₂₃BrClN₃O₂)

Examples 363-572

The compounds of this invention were synthesized pursuant to methods of Example 362 using the corresponding reactant respectively. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 7.

The following 3 compounds were obtained as by product of Compound Nos. 1415, 1416, and 1417, respectively.

1419: 7.9 mg, 38% yield; ESI/MS m/e 419.0 (C₂₀H₂₃ClN₄O₂S).

1420: 7.1 mg, 36% yield; ESI/MS m/e 399.2 (C₂₁H₂₆N₄O₂S).

1421: 7.4 mg, 37% yield; ESI/MS m/e 404.2 (C₁₉H₂₅N5o3S)

TABLE 7 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 363 1099 C₂₀H₂₀BrClFN₃O₂ 470.0 3.1 13 Example 364 1100 C₂₀H₂₀Cl₂FN₃O₂ 424.0 3.1 15 Example 365 1101 C₂₁H₂₃ClIN₃O₂ 512.0 12.5 49 Example 366 1102 C₂₁H₂₃ClN₄O₄ 431.2 7.7 36 Example 367 1103 C₂₂H₂₆BrN₃O₂ 446.0 13.8 62 Example 368 1104 C₂₁H₂₃BrFN₅O₂ 450.0 16.5 74 Example 369 1105 C₂₁H₂₃ClFN₃O₂ 404.2 14.7 73 Example 370 1106 C₂₂H₂₆IN₃O₂ 492.0 18.5 75 Example 371 1107 C₂₂H₂₆N₄O₄ 411.2 15.2 74 Example 372 1108 C₂₀H₂₅BrN₄O₃ 449.0 12.8 57 Example 373 1109 C₁₉H₂₂BrFN₄O₃ 455.0 16.2 71 Example 374 1110 C₁₉H₂₂ClFN₄O₃ 409.2 14.4 70 Example 375 1111 C₂₀H₂₅IN₄O₃ 497.0 17.9 72 Example 376 1112 C₂₀H₂₅N5O₅ 416.2 14.9 72 Example 377 1113 C₂₃H₂₇BrClN₃O₂ 494.0 16.1 65 Example 378 1114 C₂₂H₂₄BrClFN₃O₂ 498.0 20.2 81 Example 379 1115 C₂₂H₂₄Cl₂FN₃O₂ 452.2 18.6 82 Example 380 1116 C₂₃H₂₇ClIN₃O₂ 539.1 21.9 81 Example 381 1117 C₂₃H₂₇ClN₄O₄ 459.2 18.7 81 Example 382 1171 C₂₁H₂₃BrClN₃O₂ 466.0 4.9 21 Example 383 1172 C₂₂H₂₃ClN₄O₃ 427.2 16.1 75 Example 384 1173 C₂₃H₂₅ClN₄O₃ 441.2 22.8 quant Example 385 1174 C₂₀H₂₂ClFN₄O₂ 405.2 21.4 quant Example 386 1175 C₂₂H₂₆BrN₃O₂ 446.0 15.8 71 Example 387 1176 C₂₃H₂₆N₄O₃ 407.2 17.6 87 Example 388 1177 C₂₄H₂₈N₄O₃ 421.2 20.2 96 Example 389 1178 C₂₁H₂₅FN₄O₂ 385.0 16.2 84 Example 390 1179 C₂₁H₂₅N₅O₄ 412.2 2.3 11 Example 391 1180 C₂₃H₂₆N₄O₂ 391.0 21.6 quant Example 392 1181 C₂₀H₂₅BrN₄O₃ 451.0 20.1 89 Example 393 1182 C₂₁H₂₅N₅O₄ 412.2 13.3 65 Example 394 1183 C₂₂H₂₇N₅O₄ 426.2 20.9 98 Example 395 1184 C₁₉H₂₄FN₅O₃ 390.0 20.0 quant Example 396 1185 C₁₉H₂₄N₆O₅ 417.2 18.2 87 Example 397 1186 C₂₁H₂₅N₅O₃ 396.2 17.6 89 Example 398 1187 C₂₃H₂₇BrClN₃O₂ 494.0 22.1 90 Example 399 1188 C₂₄H₂₇ClN₄O₃ 455.2 17.2 76 Example 400 1189 C₂₅H₂₉ClN₄O₃ 469.2 21.1 90 Example 401 1190 C₂₂H₂₆ClFN₄O₂ 433.2 20.4 94 Example 402 1217 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 38.5 81 Example 403 1218 C₂₁H₂₃ClFN₃O₂ 404.2 35.6 88 Example 404 1219 C₂₁H₂₃Cl₂N₃O₂ 420.0 3.7  9 Example 405 1220 C₂₀H₂₂ClIN₄O₂ 513.0 53.0 quant Example 406 1221 C₂₀H₂₁ClF₂N₄O₂ 423.0 38.7 92 Example 407 1222 C₁₉H₂₃ClN₄O₂ 375.2 33.6 90 Example 408 1223 C₂₆H₂₆ClN₃O₂S 496.0 43.7 88 Example 409 1224 C₂₀H₂₁ClN₄O₅ 433.0 40.6 94 Example 410 1225 C₂₂H₂₃ClF₃N₃O₂ 454.2 18.4 41 Example 411 1226 C₂₂H₂₆FN₃O₂ 384.0 17.1 45 Example 412 1227 C₂₂H₂₆ClN₃O₂ 400.2 17.5 44 Example 413 1228 C₂₁H₂₅IN₄O₂ 493.0 23.3 47 Example 414 1229 C₂₁H₂₄F₂N₄O₂ 403.2 18.4 46 Example 415 1230 C₂₀H₂₆N₄O₂ 355.2 15.7 44 Example 416 1231 C₂₇H₂₉N₃O₂S 476.0 20.9 88 Example 417 1232 C₂₁H₂₄N₄O₅ 413.0 19.9 96 Example 418 1233 C₂₀H₂₂ClF₃N₄O₃ 459.0 19.4 85 Example 419 1234 C₂₀H₂₅FN₄O₃ 389.0 17.8 92 Example 420 1235 C₂₀H₂₅ClN₄O₃ 405.2 18.7 92 Example 421 1236 C₁₉H₂₄IN₅O₃ 498.0 23.9 96 Example 422 1237 C₁₉H₂₃F₂N₅O₃ 408.2 19.0 93 Example 423 1238 C₁₈H₂₅N₅O₃ 360.0 16.3 91 Example 424 1239 C₂₅H₂₈N₄O₃S 481.2 21.4 89 Example 425 1240 C₁₉H₂₃N₅O₆ 418.0 19.9 95 Example 426 1241 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 22.5 90 Example 427 1242 C₂₃H₂₇ClFN₃O₂ 432.2 21.2 98 Example 428 1243 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.6 96 Example 429 1244 C₂₂H₂₆ClIN₄O₂ 541.0 26.4 98 Example 430 1245 C₂₂H₂₅ClF₂N₄O₂ 451.0 21.3 94 Example 431 1246 C₂₁H₂₇ClN₄O₂ 403.2 19.4 96 Example 432 1247 C₂₈H₃₀ClN₃O₂S 524.0 24.7 94 Example 433 1248 C₂₂H₂₅ClN₄O₅ 461.0 20.7 90 Example 434 1249 C20 H20 Cl2 N4 O4 451.0 7.4 33 Example 435 1250 C21 H23 Cl N4 O4 431.2 15.5 72 Example 436 1251 C19 H22 Cl N5 O5 436.0 22.9 quant Example 437 1252 C23 H28 Cl N3 O2 414.2 17.9 86 Example 438 1253 C24 H31 N3 O2 394.2 15.8 80 Example 439 1254 C22 H30 N4 O3 399.2 17.3 87 Example 440 1255 C20 H22 Br Cl N4 O2 467.0 21.3 91 Example 441 1256 C21 H25 Br N4 O2 445.0 20.7 93 Example 442 1257 C19 H24 Br N5 O3 450.0 21.8 97 Example 443 1258 C21 H25 Cl N4 O2 401.2 18.1 90 Example 444 1259 C19 H24 Cl N5 O3 406.0 20.1 99 Example 445 1260 C23 H29 N3 O3 396.2 16.8 85 Example 446 1261 C23 H30 Cl N3 O3 432.2 19.8 92 Example 447 1262 C24 H33 N3 O3 412.2 17.4 85 Example 448 1263 C22 H32 N4 O4 417.2 18.7 90 Example 449 1264 C25 H26 Cl N3 O3 452.2 29.1 quant Example 450 1265 C26 H29 N3 O3 432.2 18.1 84 Example 451 1266 C24 H28 N4 O4 437.2 19.3 88 Example 452 1267 C₂₃H₂₂ClF₃N₄O₃ 495.2 20.6 83 Example 453 1268 C₂₁H₂₃Cl₂N₃O₃ 436.0 17.5 80 Example 454 1269 C₂₀H₂₁BrClN₃O₃ 468.0 19.2 82 Example 455 1270 C₂₀H₂₁Cl₂N₃O₃ 422.2 17.3 82 Example 456 1271 C₂₀H₂₀ClFN₄O₄ 435.0 17.1 79 Example 457 1272 C₂₄H₂₅F₃N₄O₃ 475.2 21.7 91 Example 458 1273 C₂₂H₂₆ClN₃O₃ 416.2 17.8 86 Example 459 1274 C₂₁H₂₄BrN₃O₃ 448.0 19.5 87 Example 460 1275 C₂₁H₂₄ClN₃O₃ 402.2 16.7 83 Example 461 1276 C₂₁H₂₃FN₄O₄ 415.2 18.1 87 Example 462 1277 C₂₂H₂₄F₃N₅O₄ 480.2 20.3 85 Example 463 1278 C₂₀H₂₅ClN₄O₄ 421.2 18.6 88 Example 464 1279 C₁₉H₂₃BrN₄O₄ 451.0 21.3 94 Example 465 1280 C₁₉H₂₃ClN₄O₄ 407.2 19.1 94 Example 466 1281 C₁₉H₂₂FN₅O₅ 420.2 19.1 91 Example 467 1282 C₂₅H₂₆ClF₃N₄O₃ 523.2 25.0 96 Example 468 1283 C₂₃H₂₂Cl₂N₃O₃ 464.2 12.2 53 Example 469 1284 C₂₂H₂₅BrClN₃O₃ 496.0 24.1 97 Example 470 1285 C₂₂H₂₅Cl₂N₃O₃ 450.2 21.8 97 Example 471 1321 C₂₀H₂₀BrCl₂N₃O₂ 486.0 5.1 21 Example 472 1322 C₂₁H₂₃Cl₂N₃O₂ 420.0 10.5 50 Example 473 1323 C₂₀H₂₀Cl₂IN₃O₂ 532.0 7.1 27 Example 474 1324 C₂₁H₂₄ClN₃O₃ 402.2 22.2 quant Example 475 1325 C₂₇H₂₆ClN₃O₃ 476.0 22.2 93 Example 476 1326 C₂₀H₂₁ClIN₃O₃ 514.0 26.9 quant Example 477 1327 C₂₁H₂₅ClN₄O₂ 401.2 24.2 quant Example 478 1328 C₂₁H₂₃BrClN₃O₂ 466.0 23.1 99 Example 479 1329 C₂₂H₂₆ClN₃O₂ 400.2 16.4 82 Example 480 1330 C₂₁H₂₃ClIN₃O₂ 512.2 20.8 81 Example 481 1331 C₂₁H₂₄N₃O₃ 382.2 19.6 quant Example 482 1332 C₂₈H₂₉N₃O₃ 456.2 21.1 93 Example 483 1333 C₂₁H₂₄IN₃O₃ 494.0 25.3 quant Example 484 1334 C₂₂H₂₈N₄O₂ 381.2 19.0 quant Example 485 1335 C₁₉H₂₂BrClN₄O₃ 471.0 25.8 quant Example 486 1336 C₂₀H₂₅ClN₄O₃ 405.2 18.5 91 Example 487 1337 C₁₉H₂₃ClIN₄O₃ 517.0 23.1 89 Example 488 1338 C₂₀H₂₆N₄O₄ 387.2 20.6 quant Example 489 1339 C₂₆H₂₈N₄O₄ 461.2 23.7 quant Example 490 1340 C₁₉H₂₃IN₄O₄ 499.0 28.2 quant Example 491 1341 C₂₀H₂₆N₄O₄ 386.0 20.5 quant Example 492 1342 C₂₂H₂₄BrCl₂N₃O₂ 514.0 27.2 quant Example 493 1343 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.4 95 Example 494 1344 C₂₂H₂₄Cl₂IN₃O₂ 560.0 27.0 96 Example 495 1345 C₂₃H₂₈ClN₃O₃ 430.2 23.8 quant Example 496 1346 C₂₂H₂₅ClIN₃O₃ 542.0 29.4 quant Example 497 1347 C₁₉H₂₃ClN₃O₂S 392.0 16.9 43 Example 498 1348 C₂₀H₂₅N₃O₂S 372.2 6.9 19 Example 499 1349 C₁₈H₂₄N₄O₃S 377.2 8.1 43 Example 500 1350 C₂₁H₂₆ClN₃O₂S 420.0 13.0 62 Example 501 1351 C₂₂H₂₄BrClN₄O₃ 509.2 5.0 10 Example 502 1352 C₂₃H₂₇BrN₄O₃ 489.2 3.6 15 Example 503 1353 C₂₁H₂₆BrN₅O₄ 494.0 2.8 11 Example 504 1354 C₂₄H₂₈BrClN₄O₃ 537.2 5.2 19 Example 505 1355 C21 H22 Cl N5 O2 412.0 25.5 quant Example 506 1356 C22 H25 N5 O2 392.0 16.5 84 Example 507 1357 C20 H24 N6 O3 397.2 19.9 quant Example 508 1358 C23 H26 Cl N5 O2 440.2 21.8 99 Example 509 1368 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 18.4 78 Example 510 1369 C₂₄H₂₄ClF₆IN₃O₄ 568.0 24.1 85 Example 511 1370 C₁₈H₁₉BrClN₃O₂S 458.0 19.4 85 Example 512 1371 C₂₆H₂₆ClN₃O₄S 512.2 22.1 86 Example 513 1372 C₂₆H₂₆ClN₃O₂ 448.0 19.1 85 Example 514 1373 C₂₂H₂₃ClF₃N₃O₂ 454.2 16.2 71 Example 515 1374 C₂₅H₂₇F₆IN₃O₄ 548.2 22.1 81 Example 516 1375 C₁₉H₂₂BrN₃O₂S 436.0 17.1 78 Example 517 1376 C₂₇H₂₉N₃O₄S 492.0 19.4 79 Example 518 1377 C₂₇H₂₉N₃O₂ 428.2 18.1 85 Example 519 1378 C₂₀H₂₂ClF₃N₄O₃ 459.0 17.3 75 Example 520 1379 C₂₃H₂₆F₆IN₄O₅ 553.2 21.0 76 Example 521 1380 C₁₇H₂₁BrN₄O₃S 443.0 16.4 74 Example 522 1381 C₂₅H₂₈N₄O₅S 497.0 18.4 74 Example 523 1382 C₂₅H₂₈N₄O₃ 433.2 17.3 80 Example 524 1383 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 20.0 80 Example 525 1384 C₂₀H₂₃BrClN₃O₂S 486.0 21.0 87 Example 526 1385 C₂₈H₃₀ClN₃O₄S 540.2 23.8 88 Example 527 1386 C₂₈H₃₀ClN₃O₂ 476.0 20.0 84 Example 528 1411 C₂₂H₂₄Cl₂N₄O₃ 463.0 0.4  2 Example 529 1412 C₂₃H₂₇ClN₄O₂ 443.0 1.3  6 Example 530 1413 C₂₁H₂₆ClN₅O₄ 448.0 1.1  5 Example 531 1414 C₂₄H₂₂Cl₂N₄O₃ 491.0 0.8  3 Example 532 1415 C₂₁H₂₂ClN₅O₂S 444.0 6.8 31 Example 533 1416 C₂₂H₂₅N₅O₂S 424.0 4.8 23 Example 534 1417 C₂₀H₂₄N₆O₃S 429.2 4.5 21 Example 535 1418 C₂₃H₂₆ClN₅O₂S 472.0 10.4 44 Example 536 1423 C27 H26 Cl N3 O3 476.0 23.9 quant Example 537 1424 C27 H29 N3 O4 S 456.2 28.0 quant Example 538 1425 C26 H28 N4 O4 461.2 22.3 97 Example 539 1426 C29 H30 Cl N3 O3 504.2 26.8 quant Example 540 1583 C21 H22 Cl F3 N4 O2 455.0 14.6 64 Example 541 1584 C21 H22 Cl F3 N4 O3 471.0 17.4 74 Example 542 1585 C19 H20 Br Cl N4 O2 453.0 15.6 69 Example 543 1586 C19 H20 Cl2 N4 O2 407.2 2.3 11 Example 544 1587 C26 H26 Cl N3 O3 464.0 15.4 66 Example 545 1588 C20 H23 Cl N4 O2 387.0 14.8 77 Example 546 1589 C22 H25 F3 N4 O2 435.2 11.1 51 Example 547 1590 C20 H25 F3 N4 O3 451.2 16.3 72 Example 548 1591 C20 H23 Br N4 O2 433.0 15.4 71 Example 549 1592 C20 H23 Cl N4 O2 387.0 15.6 81 Example 550 1593 C27 H29 N3 O3 444.2 14.8 67 Example 551 1594 C20 H24 F3 N5 O3 440.2 16.2 74 Example 552 1595 C20 H24 F3 N5 O4 456.2 15.4 68 Example 553 1596 Cl8 H22 Br N5 O3 436.0 15.6 72 Example 554 1597 Cl8 H22 Cl N5 O3 391.8 14.4 73 Example 555 1598 C25 H28 N4 O4 449.2 15.9 71 Example 556 1599 C19 H25 N5 O3 372.2 15.8 85 Example 557 1606 C21 H21 Cl F3 N3 O2 S 472.0 17.0 72 Example 558 1607 C21 H21 Cl F3 N3 O2 S 452.2 15.3 68 Example 559 1608 C20 H23 F3 N4 O3 S 457.2 15.9 70 Example 560 1660 C21 H22 Br F3 N4 O2 501.0 19.0 76 Example 561 1661 C21 H22 Br F3 N4 O3 517.0 16.2 63 Example 562 1662 C20 H21 Br F2 N4 O2 469.0 15.1 65 Example 563 1663 C20 H22 Br Cl N4 O2 467.0 14.5 62 Example 564 1692 C20 H23 Br2 N3 O3 514 7.3 28 Example 565 1693 C22 H26 F2 N4 O2 417 16.2 78 Example 566 1694 C22 H27 F N4 O2 399 21.8 quant Example 567 1695 C22 H27 Br N4 O2 459 24.5 quant Example 568 1696 C22 H27 I N4 O2 507 27.4 quant Example 569 1697 C22 H27 Cl N4 O2 415 22.1 quant Example 570 1698 C23 H27 F3 N4 O3 465 24.3 quant Example 571 1699 C23 H27 F3 N4 O2 449 25.3 quant Example 572 1700 C22 H25 Br Cl N3 O2 480 17.8 74

For example, Compound No. 1583 showed the following NMR spectra: ¹H NMR (400 MHz, CD₃OD) δ 1.64-1.72 (m, 1 H), 2.20-2.30 (m, 1 H), 2.41-2.51 (m, 2 H), 2.71-2.78 (m, 2 H), 3.59 (dd, J=15.4, 12.9 Hz, 2 H), 3.94 (s, 2 H), 4.35-4.41 (m, 1 H), 6.82 (d, J=8.6 Hz, 1 H), 7.29 (s, 4 H), 7.40 (dd, J=8.6, 1.7 Hz, 1 H), 7.85 (d, J=0.96 Hz, 1 H).

Reference Example 4 Preparation of (S)-3-[N-{3(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine

A suspension of (S)-1-(4-chlorobenzyl)-3-[N-{3(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (2.93 g, 6.66 mmol) and Pd(OH)₂ in 5% HCO₂H/methanol (70 mL) was stirred at 60° C. for 3 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 2 N aqueous NaOH solution (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, AcOEt/MeOH/Et₃N=85/10/5-60/30/5) gave (S)-3-[N-{3(trifluoromethyl}benzoyl)glycyl]aminopyrrolidine (1.70 g, 81%) as an oil: ¹H NMR (CDCl₃, 270 MHz) δ 1.76 (d, J=7.3 Hz, 1 H), 2.07-2.25 (m, 1 H), 2.81-2.98 (m, 2 H), 3.02-3.11 (m, 2 H), 4.12 (s, 2 H), 4.41 (br, 1 H), 6.90 (br, 1 H), 7.45 (br, 1 H), 7.58 (dd, J=7.3 and 7.3 Hz, 1 H), 7.77 (d, J =7.3 Hz, 1 H), 8.02 (d, J=7.3 Hz, 1 H), 8.11 (s, 1 H); ESI/MS m/e 316.0 (M⁺+H, C₁₄H₁₆F₃N₃O₂).

(R)-3-[N-{3-(Trifluoromethyl)benzoyl}glycyl]aminopyrrolidine was also prepared pursuant to the above method using the corresponding reactant: 1.49g, 68%; The product showed the same ¹H NMR and ESI/MS with those of (S)-isomer.

(R)-3-[N-{2-Amino-5-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine was also prepared pursuant to the above method using the corresponding reactant: 316 mg, 93%; ESI/MS m/e 331.2 (M⁺+H, C₁₄H₁₇F₃N₄O₂).

(R)-3-[N-{2-(tert-Butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl}glycyl]aminopyrrolidine was also prepared pursuant to the above method using the corresponding reactant: quant; ¹H NMR (CDCl₃, 400 MHz) δ 1.51 (s, 9 H), 1.60-1.70 (m, 2 H), 2.10-2.25 (m, 1 H), 2.80-2.88 (m, 1 H), 2.89-2.98 (m, 1 H), 3.04-3.18 (m, 2 H), 4.05 (d, J=4.9 Hz, 2 H), 4.43 (br, 1 H), 6.15 (br, 1 H), 7.03 (br, 1 H), 7.32 (d, J=9.3 Hz, 1 H), 7.38 (s, 1 H), 8.42 (d, J=9.3 Hz, 1 H).

Example 573 Preparation of (R)-3-[{N-(2-(tert-Butoxycarbonylamino)-5-trifluoromethylbenzonyl)glycyl}amino]-1-(4-cholobenzyl)pyrrolidine

A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (5.0 g, 18.7 mmol) in dichloromethane (100 mL) was treated with Et₃N (2.9 mL, 20.5 mmol), 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (6.27 g, 20.5 mmol), EDCI (3.9 g, 20.5 mmol) and HOBt (2.8 g, 20.5 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added 2 N aqueous NaOH solution (80 mL) and the mixture was extracted with dichloromethane. The extract was dried over anhydrous Na₂SO₄, filtered, and evaporated. Column chromatography (SiO₂, hexane/ethyl acetate=1/1-1/4) afforded (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chlorobenzyl)pyrrolidine (9.41 g, 91%) as a white amorphous solid: ESI/MS m/e 555.2 (M⁺H, C₂₆H₊ClF₃N₄O₄).

Reference Example 5 Preparation of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine

A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chlorobenzyl)pyrrolidine (6.3 g, 11.4 mmol), Pd(OH)₂ (1.68 g), HCO₂H (3.7 mL), and methanol (80 mL) was stirred at 50° C. overnight. After the mixture was cooled to room temperature, the Pd catalyst was filtered off through Celite and the filtrate was concentrated. Column chromatography (SiO₂, AcOEt, AcOEt/MeOH=5/1-4/1) gave (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (4.42 g, 90%) as a white solid:

¹H NMR (CDCl₃, 400 MHz) δ 1.48 (s, 9 H), 2.0-2.4 (m, 2 H), 3.42-3.71 (m, 5 H), 4.00-4.22 (m, 2 H), 4.56 (br, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.93 (s, 1 H), 8.17 (br, 1 H), 8.33 (d, J=9.0 Hz, 1 H), 8.45 (br, 1 H).

Example 574 Preparation of (S)-1-Benzyl-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (Compound No. 239)

A solution of (S)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (0.060 mmol) in CH₃CN (1.1 mL) and (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 30 mg) were added to a solution of benzyl bromide (0.050 mmol) in CH₃CN (0.4 mL). The reaction mixture was stirred at 45° C. for 5 h. After the mixture was cooled to room temperature, the resin was removed by filtration and the filtrate was concentrated. The residue was resolved in CH₃CN (1.0 mL) and phenyl isocyanate (0.008 mL, 0.05 mmol) was added. The mixture was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH₃OH (15 mL). Product was eluted off using 2 N NH₃ in CH₃OH (6 mL) and concentrated to afford (S)-1-benzyl-3-[N{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (compound No.239) (9.0 mg, 44%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 406.0 (M⁺+H, C₂₁H₂₂F₃N₃O₂).

Example 575 Preparation of (R)-1-(4-Butylbenzyl)-3-[{N-(3-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1648)

To a mixture of (R)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 4-butylbenzaldehyde (0.18 mmol), NaBH₃CN (0.23 mmol), and methanol (1.85 mL) was added acetic acid (0.060 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (15 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford (R)-1-(4-butylbenzyl)-3-[{N-(3-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1648) (20.6 mg, 89%): The purity was determined by RPLC/MS (91%); ESI/MS m/e 462.2 (M⁺+H, C₂₅H₃₀F₃N₃O₂).

Examples 576-738

The compounds of this invention were synthesized pursuant to methods of Examples 574 or 575 using the corresponding reactant respectively. Preparative TLC or chromatography (HPLC-C₁₈), if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 8.

TABLE 8 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 576  240 C₂₁H₂₁F₄N₃O₂ 424.0 10.2 48 Example 577  241 C₂₁H₂₁ClF₃N₃O₂ 440.0 12.1 55 Example 578  242 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.9 59 Example 579  243 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.8 58 Example 580  244 C₂₂H₂₄F₃N₃O₂ 420.0 13.1 62 Example 581  245 C₂₁H₂₁F₄N₃O₂ 424.0 11.9 56 Example 582  246 C₂₁H₂₁ClF₃N₃O₂ 440.0 8.5 39 Example 583  247 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 10.5 44 Example 584  248 C₂₂H₂₄CF₃N₃O₂ 436.0 11.0 51 Example 585  249 C₂₂H₂₁ClF₆N₃O₂ 474.0 12.8 54 Example 586  250 C₂₂H₂₄F₃N₃O₂ 420.0 11.0 52 Example 587  251 C₂₁H₂₁F₄N₃O₂ 424.0 13.5 64 Example 588  252 C₂₂H₂₄F₃N₃O₃ 436.0 11.8 54 Example 589  253 C₂₂H₂₄F₃N₃O₂ 420.0 11.1 53 Example 590  254 C₂₁H₂₀ClF₃N₄O₄ 485.0 2.4 10 Example 591  255 C₂₁H₂₁F₃N₄O₄ 451.0 12.2 54 Example 592  256 C₂₁H₂₁F₃N₄O₄ 451.0 11.4 51 Example 593  257 C₂₂H₂₁F₆N₃O₂ 474.0 11.1 47 Example 594  258 C₂₄H₂₆F₃N₃O₄ 478.0 15.3 64 Example 595  259 C₂₂H₂₃ClF₃N₃O₂ 420.0 6.4 31 Example 596  260 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 12.1 51 Example 597  261 C₂₂H₂₁ClF₆N₃O₂ 474.0 13.6 57 Example 598  262 C₂₁H₂₁BrF₃N₃O₂ 484.0 15.2 63 Example 599  263 C₂₁H₂₁BrF₃N₃O₂ 484.0 14.5 60 Example 600  264 C₂₇H₂₆F₃N₃O₃ 498.0 9.3 37 Example 601  265 C₂₁H₂₁BrF₃N₃O₂ 484.0 11.6 48 Example 602  266 C₂₂H₂₂F₃N₃O₄ 450.0 8.9 40 Example 603  267 C₂₂H₂₄F₃N₃O₃ 436.0 10.3 47 Example 604  268 C₂₃H₂₅F₃N₄O₃ 463.0 6.3 27 Example 605  269 C₂₂H₂₄F₃N₃O₄S 484.0 8.0 33 Example 606  270 C₂₃H₂₄F₃N₃O₄ 464.0 8.9 38 Example 607  271 C₂₁H₂₆F₅N₃O₂ 442.0 6.1 28 Example 608  272 C₂₁H₂₂F₃N₃O₃ 422.0 13.6 59 Example 609  273 C₂₂H₂₁F₃N₄O₂ 431.0 12.6 59 Example 610  274 C₂₂H₂₁F₃N₄O₂ 431.0 7.7 36 Example 611  275 C₂₂H₂₁F₃N₄O₂ 431.0 12.7 59 Example 612  276 C₂₁H₂₀F₅N₃O₂ 442.0 11.7 53 Example 613  277 C₂₇H₂₆F₃N₃O₂ 482.0 9.5 39 Example 614  278 C₂₃H₂₄F₃N₃O₄ 464.0 13.0 56 Example 615  279 C₂₂H₂₁F₆N₃O₃ 490.0 10.4 42 Example 616  280 C₂₂H₂₁F₆N₂O₃ 490.0 12.0 49 Example 617  281 C₂₂H₂₂F₃N₃O₄ 450.0 4.9 22 Example 618  282 C₂₅H₃₀F₃N₃O₂ 462.0 12.0 52 Example 619  283 C₂₀H₂₃F₃N₄O₃ 425.0 8.1 38 Example 620  284 C₂₇H₂₅ClF₃N₃O₂ 516.0 4.8 19 Example 621  285 C₂₁H₂₂F₃N₃O₂ 406.0 4.8 24 Example 622  286 C₂₁H₂₁F₄N₃O₂ 424.0 4.5 21 Example 623  287 C₂₁H₂₁ClF₃N₃O₂ 440.0 5.8 26 Example 624  288 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 8.1 34 Example 625  289 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 8.0 34 Example 626  290 C₂₂H₂₄F₃N₃O₂ 420.0 6.0 29 Example 627  291 C₂₁H₂₁F₄N₃O₂ 424.0 6.2 29 Example 628  292 C₂₁H₂₁ClF₃N₃O₂ 440.0 4.5 20 Example 629  293 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 5.1 22 Example 630  294 C₂₂H₂₄CF₃N₃O₃ 436.0 4.2 19 Example 631  295 C₂₂H₂₁ClF₆N₃O₂ 474.0 6.0 25 Example 632  296 C₂₂H₂₄F₃N₃O₂ 420.0 4.3 21 Example 633  297 C₂₁H₂₁F₄N₃O₂ 424.0 8.2 39 Example 634  298 C₂₂H₂₄F₃N₃O₃ 436.0 12.2 56 Example 635  299 C₂₂H₂₄F₃N₃O₂ 420.0 8.1 39 Example 636  300 C₂₁H₂₀ClF₃N₄O₄ 485.0 13.7 57 Example 637  301 C₂₁H₂₁F₃N₄O₄ 451.0 15.1 67 Example 638  302 C₂₁H₂₁F₃N₄O₄ 451.0 16.6 74 Example 639  303 C₂₂H₂₁F₆N₃O₂ 474.0 12.6 53 Example 640  304 C₂₄H₂₆F₃N₃O₄ 478.0 14.5 61 Example 641  305 C₂₂H₂₃ClF₃N₃O₂ 420.0 8.4 37 Example 642  306 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.5 57 Example 643  307 C₂₂H₂₁ClF₆N₃O₂ 474.0 3.7 16 Example 644  308 C₂₁H₂₁BrF₃N₃O₂ 484.0 7.2 30 Example 645  309 C₂₁H₂₁BrF₃N₃O₂ 484.0 6.7 28 Example 646  310 C₂₇H₂₆F₃N₃O₂ 498.0 4.2 17 Example 647  311 C₂₁H₂₁BrF₃N₃O₂ 484.0 6.3 26 Example 648  312 C₂₂H₂₂F₃N₃O₄ 450.0 2.4 11 Example 649  313 C₂₂H₂₄F₃N₃O₃ 436.0 1.9  9 Example 650  314 C₂₃H₂₅F₃N₄O₃ 463.0 5.0 22 Example 651  315 C₂₂H₂₄F₃N₃O₄S 484.0 2.5 10 Example 652  316 C₂₃H₂₄F₃N₃O₄ 464.0 3.3 14 Example 653  317 C₂₁H₂₀F₅N₃O₂ 442.0 4.5 20 Example 654  318 C₂₁H₂₂F₃N₃O₃ 422.0 7.9 34 Example 655  319 C₂₂H₂₁F₃N₄O₂ 431.0 6.5 30 Example 656  320 C₂₂H₂₁F₃N₄O₂ 431.0 14.2 66 Example 657  321 C₂₂H₂₁F₃N₄O₂ 431.0 14.9 69 Example 658  322 C₂₁H₂₀F₅N₃O₂ 442.0 13.6 62 Example 659  323 C₂₇H₂₆F₃N₃O₂ 482.0 3.9 16 Example 660  324 C₂₃H₂₄F₃N₃O₄ 464.0 15.2 66 Example 661  325 C₂₂H₂₁F₆N₃O₃ 490.0 16.1 66 Example 662  326 C₂₂H₂₁F₆N₃O₃ 490.0 13.6 56 Example 663  327 C₂₂H₂₂F₃N₃O₄ 450.0 5.4 24 Example 664  328 C₂₅H₃₁F₃N₃O₂ 462.0 10.9 47 Example 665  329 C₂₀H₂₃F₃N₄O₃ 425.0 12.0 57 Example 666  986 C27 H25 Cl F3 N3 O2 516.0 1.5  6 Example 667 1118 C28 H27 F3 N4 O3 525   21.5 62 Example 668 1119 C22 H24 F3 N3 O2 S 452   16.9 57 Example 669 1120 C23 H26 F3 N3 O4 466   20.5 67 Example 670 1121 C22 H23 F3 N4 O4 465   16.8 55 Example 671 1122 C28 H36 F3 N3 O2 504   21.0 63 Example 672 1123 C25 H23 Br F3 N3 O2 534   26.6 75 Example 673 1124 C19 H19 F3 N4 O5 441   21.3 73 Example 674 1133 C23 H26 F3 N3 O4 467   33.6 84 Example 675 1134 C24 H28 F3 N3 O5 496   34.8 82 Example 676 1135 C22 H21 F3 N4 O6 495   32.6 77 Example 677 1136 C23 H24 F3 N3 O5 480   36.6 89 Example 678 1137 C22 H21 Br F3 N3 O4 529   30.8 69 Example 679 1138 C24 H26 F3 N3 O2 446   32.7 86 Example 680 1139 C22 H24 F3 N3 O2 420   18.6 51 Example 681 1140 C21 H20 F3 N5 O6 496   20.5 49 Example 682 1141 C25 H24 F3 N3 O2 456   22.5 58 Example 683 1142 C25 H24 F3 N3 O2 456   21.6 55 Example 684 1143 C35 H34 F3 N3 O4 618   27.3 53 Example 685 1144 C23 H26 F3 N3 O4 466   25.5 64 Example 686 1145 C23 H25 F3 N4 O6 511   38.0 88 Example 687 1146 C28 H28 F3 N3 O3 512   38.3 89 Example 688 1147 C23 H25 F3 N4 O3 463   27.1 62 Example 689 1148 C27 H26 F3 N3 O2 482   22.4 57 Example 690 1161 C22 H24 F3 N3 O4 452   13.5 58 Example 691 1162 C24 H28 F3 N3 O3 464   16.7 70 Example 692 1163 C22 H23 F4 N3 O3 454   15.8 68 Example 693 1164 C23 H26 F3 N3 O3 450   15.7 68 Example 694 1165 C23 H24 F3 N3 O4 464   16.3 68 Example 695 1166 C22 H23 Br F3 N3 O3 513   15.0 57 Example 696 1168 C17 H17 Cl F3 N5 O2 S 448   6.9* 23 Example 697 1169 C20 H22 F3 N5 O3 S 470   1.7*  6 Example 698 1170 C22 H22 F3 N5 O2 446   2.3*  8 Example 699 1286 C26 H33 F3 N4 O3 507   25.3* 51 Example 700 1287 C21 H20 F3 N5 O6 496   4.0*  8 Example 701 1288 C22 H24 F3 N3 O4 452   3.6* 13 Example 702 1298 C23 H25 Br F3 N3 O4 544   28.4 quant Example 703 1299 C24 H28 F3 N3 O5 496   1.4  6 Example 704 1300 C23 H26 F3 N3 O4 466   7.3 33 Example 705 1301 C24 H28 F3 N3 O5 496   12.6 53 Example 706 1302 C24 H28 F3 N3 O3 464   24.5 quant Example 707 1303 C23 H25 Br F3 N3 O4 544   22.2 86 Example 708 1304 C29 H30 F3 N3 O4 542   28.6 quant Example 709 1305 C26 H26 F3 N3 O3 486   35.4 quant Example 710 1306 C24 H28 F3 N3 O4 480   8.1 35 Example 711 1307 C23 H26 F3 N3 O5 482   27.9 quant Example 712 1308 C23 H24 F3 N3 O3 448   5.9 28 Example 713 1309 C23 H25 F3 I N3 O4 592   24.0 85 Example 714 1310 C22 H24 F3 N3 O4 452   3.4 16 Example 715 1311 C22 H22 F3 N3 O4 450   3.4 16 Example 716 1312 C21 H21 F3 I N3 O2 532   18.1 72 Example 717 1313 C21 H21 Br F3 N3 O2 484   17.4 76 Example 718 1314 C19 H19 F3 N4 O4 S 457   16.8 77 Example 719 1315 C20 H22 F3 N3 O3 410   13.6 70 Example 720 1316 C22 H20 Cl F6 N3 O2 508   18.6 77 Example 721 1317 C21 H20 Cl F3 N4 O4 485   17.0 74 Example 722 1318 C21 H20 Cl F4 N3 O2 458   17.0 78 Example 723 1319 C21 H20 Cl F4 N3 O2 458   17.6 81 Example 724 1320 C21 H20 Br F4 N3 O2 502   18.5 77 Example 725 1390 C26 H32 F3 N3 O2 476   16.1 51 Example 726 1391 C23 H26 F3 N3 O2 434   20.0 76 Example 727 1392 C22 H23 Cl F3 N3 O2 454   20.0 67 Example 728 1393 C23 H26 F3 N3 O2 434   20.1 70 Example 729 1394 C22 H23 F3 N4 O4 465   18.4 60 Example 730 1395 C23 H24 F3 N3 O2 432   21.4 75 Example 731 1396 C26 H26 F3 N3 O2 470   20.4 66 Example 732 1397 C21 H20 Br2 F3 N3 O2 562   14.5 54 Example 733 1398 C22 H22 Cl2 F3 N3 O2 488   10.8 47 Example 734 1399 C22 H22 Cl2 F3 N3 O2 488   9.4 40 Example 735 1400 C22 H23 Cl F3 N3 O2 454   19.1 88 Example 736 1614 C22 H21 F6 N3 S 506.0 24.2 96 Example 737 2050 C20 H22 F3 N3 O2 S 426   6.0 30 Example 738 2051 C21 H23 F3 N4 O2 421   6.5 32 *Yield of TFA salt.

Examples 739-748

The compounds of this invention were synthesized pursuant to methods of Example 738 using the corresponding reactant respectively. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 9.

TABLE 9 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 739 1650 C24 H28 F3 N3 O2 448.0 20.4 91   Example 740 1706 C23 H25 F3 N4 O3 463.2 3.7 11   Example 741 1707 C22 H25 F3 N4 O2 S 467.0 10.3 29   Example 742 1708 C23 H27 F3 N4 O2 449.2 11.4 34   Example 743 1709 C24 H29 F3 N4 O2 463.2 15.2 44   Example 744 1775 C22 H25 F3 N4 O4 467.2 9.2 26.3 Example 745 1776 C22 H25 F3 N4 O4 467.2 8.9 25.4 Example 746 1787 C24 H29 F3 N4 O2 463.2 5.6 16.1 Example 747 1802 C23 H27 F3 N4 O4 481.2 11.7 32.5 Example 748 1803 C22 H25 F3 N4 O3 451.2 9.6 28.4

Example 749 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethoxybenzoyl) glycyl}amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compound No. 1896)

To a mixture of (R)-3-[N-{2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 3-hydroxy-4-methoxybenzaldehyde (0.060 mmol), NaBH₃CN (0.15 mmol), and methanol (1.3 mL) was added acetic acid (0.050 mL). The reaction mixture was stirred at 60° C. for 8 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (10 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane and the solution was stirred overnight at room temperature. Concentration and preparative TLC gave (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compound No. 1896) (9.1 mg, 38%): The purity was determined by RPLC/MS (93%); ESI/MS m/e 483 (M⁺+H, C₂₂H₂₅F₃N₄O₅).

Examples 750-757

The compounds of this invention were synthesized pursuant to methods of Example 749 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 10.

TABLE 10 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 750 1897 C22 H25 F3 N4 O3 S 483   22.7 94.1 Example 751 1898 C23 H27 F3 N4 O3 465   12.2 52.5 Example 752 1899 C24 H29 F3 N4 O3 479   14.4 60.2 Example 753 1900 C22 H25 F3 N4 O5 483   2.6 10.8 Example 754 1901 C24 H29 F3 N4 O3 479   14.5 60.6 Example 755 1902 C23 H25 F3 N4 O4 479   12.0 50.2 Example 756 1915 C23 H27 F3 N4 O5 467.2 2.5  6.7 Example 757 1916 C22 H25 F3 N4 O4 467.2 3.1  8.9

Example 758 Preparation of (R)-3-[{N-(2-Amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701)

A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]pyrrolidine (0.05 mmol), 4-vinylbenzyl chloride (9.9 mg, 0.065 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH₃OH (15 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701) (19.6 mg, 88%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 547.2 (M⁺+H, C₂₃H₂₅ClF₃N₄O₂).

Examples 759-762

The compounds of this invention were synthesized pursuant to methods of Example 758 using the corresponding reactant respectively. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 11.

TABLE 11 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 759 1702 C22 H25 F3 N4 O3 451.2 5.3 24 Example 760 1703 C22 H23 F3 N4 O4 465.2 5.0 22 Example 761 1704 C21 H23 F3 N4 O3 437.2 20.9 96 Example 762 1705 C21 H21 Cl2 F3 N4 O2 489.2 9.3 38

Example 763 Preparation of (R)-3-[{N-(2-Amino-5-(trifluoromethoxy) benzoyl)glycyl}amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compound No. 1905)

A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethoxy)benzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 2,4-dichlorobenzyl chloride (0.060 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl₃/CH₃OH (10 mL) and CH₃OH (10 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL), and the solution was stirred overnight at room temperature. Concentration and preparative TLC afforded (R)-3-[{N-(2-amino-5-(trifluoromethoxy)benzoyl)glycyl}amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compound No. 1905) (17.6 mg, 70%): The purity was determined by RPLC/MS (93%); ESI/MS m/e 505 (M⁺+H, C₂₁H₂₁Cl₂F₃N₄O₃).

Examples 764-770

The compounds of this invention were synthesized pursuant to methods of Example 763 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 12.

TABLE 12 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 764 1906 C22 H23 F3 N4 O5 481 9.4 39.1 Example 765 1907 C21 H23 F3 N4 O4 453 7.5 33.2 Example 766 1908 C22 H25 F3 N4 O4 467 7.7 33.0 Example 767 2180 C22 H24 Cl F3 N4 O2 469 1.3 26   Example 768 2181 C23 H25 F3 N6 O3 491 4.3 52   Example 769 2182 C19 H22 F3 N5 O2 S 442 7.0 51   Example 770 1909 C23 H25 F3 N4 O3 463 8.7 37.6

Example 771 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethoxybenzoyl) glycyl}amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compound No. 1921)

A mixture of (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl₃/CH₃OH (10 mL) and CH₃OH (10 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd-C (15 mg), and the mixture was stirred under H₂ at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded (R)-3[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compound No. 1921) (2.2 mg, 6%): The purity was determined by RPLC/MS (81%); ESI/MS m/e 486.2 (M⁺+H, C₂₁H₂₃ClF₃N₅O₃).

Example 772 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120)

To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-bromo-2 fluorobenzaldehyde (0.15 mmol), methanol (1.5 mL), and acetic acid (0.016 mL) was added NaBH₃CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CHOH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature for 5 h and concentrated. The residue was dissolved in methanol, loaded onto Varian™0 SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH. in CH₃OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate (0.5 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (6 mL), and concentrated to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120) (16.0 mg, 31%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 517.0 (M⁺+H, C₂₁H₂₁BrF₄N₄O₂).

Examples 773-793

The compounds of this invention were synthesized pursuant to methods of Example 772 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 13.

TABLE 13 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 773 2083 C22 H24 Br F3 N4 O4 545.2 2.9 11 Example 774 2084 C23 H27 F3 N4 O5 497.2 5.1 21 Example 775 2085 C22 H25 F3 N4 O4 467.2 3.1 13 Example 776 2086 C21 H22 Cl F3 N4 O3 471.0 4.6 20 Example 777 2087 C23 H28 F3 N5 O2 464.2 5.6 24 Example 778 2088 C25 H32 F3 N5 O2 492.2 5.9 24 Example 779 2089 C21 H21 F5 N4 O2 457.2 4.5 20 Example 780 2090 C27 H27 F3 N4 O3 513.2 8.0 31 Example 781 2118 C21 H23 F3 N4 O4 453.1 2.7 12 Example 782 2119 C21 H23 F3 N4 O4 453.1 4.3 19 Example 783 2121 C22 H25 F3 N4 O4 467.0 1.2  2 Example 784 2122 C21 H21 Cl F4 N4 O2 472.9 13.1 28 Example 785 2123 C22 H22 F3 N5 O6 510.1 13.1 51 Example 786 2124 C21 H21 Cl F3 N5 O4 500.1 15.6 62 Example 787 2125 C22 H24 F3 N5 O5 496.0 16.0 65 Example 788 2126 C22 H24 F3 N5 O4 480.1 15.6 65 Example 789 2137 C22 H24 Cl F3 N4 O2 469.2 2.6 11 Example 790 2138 C26 H29 F3 N6 O2 515.3 25.1 98 Example 791 2139 C20 H24 Cl F3 N6 O2 473.2 25.0 98 Example 792 2149 C21 H22 F3 N5 O5 482.3 4.9 34 Example 793 2157 C22 H25 F3 N4 O3 451.2 15.5 70

Example 794 Preparation of (R)-3-[{N-(2-Amino-5trifluoromethylbenzoyl)glycyl}amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compound No. 2175)

(R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL) and 2,4-dimethoxy-5-pyrimidine carboxaldehyde (6.7 mg, 0.04 mmol) was added followed by sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol). The mixture was stirred at room temperature for 24 h and evaporated. The residue was then dissolved in dichloromethane (1 mL) and washed with 1 N NaOH solution (1 mL). The organic phase was recovered and evaporated then treated with 25% trifluoroacetic acid in dichloromethane (1 mL) for 1 h at room temperature and evaporated. The residue was purified using LC/MS to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compound No. 2175) (18.6 mg, 78%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 483 (M⁺+H, C₂₁H₂₅F₃N₆O₄).

Examples 795-803

The compounds of this invention were synthesized pursuant to methods of Example 794 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 14.

TABLE 14 Com- ESI/ pound MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 795 2165 C18 H21 F3 N6 O2 411 2.0 27 Example 796 2166 C18 H20 F3 N5 O2 S 428 9.9 66 Example 797 2167 C24 H25 F3 N6 O2 487 15.1 73 Example 798 2169 C24 H29 F3 N4 O2 463 1.2 24 Example 799 2170 C26 H25 Cl F3 N5 O2 520 6.0 40 Example 800 2171 C19 H23 F3 N6 O2 425 16.8 88 Example 801 2174 C23 H24 Br F3 N4 O2 S2 591 5.3 53 Example 802 2178 C25 H28 F3 N5 O4 518 5.4 62 Example 803 2179 C25 H28 F3 N5 O3 502 6.3 60

Example 804 Preparation of (R)-1-(2-Amino-4,5-methylenedioxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2127)

A mixture of (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (30.5 mg), 10% Pd-activated carbone (6 mg), and methanol (3 mL) was stirred under a hydrogen atmosphere at room temperature for 10 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. Solid phase extraction (Bond Elut™ SI, 20% methanol/AcOEt) afforded (R)-1(2-amino-4,5-methylenedioxybenzyl)-3-[{N-(2-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2127) (21.9 mg, 76%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 480.1 (M⁺+H, C₂₂H₂₄F₃N₅O₄).

Examples 805 and 806

The compounds of this invention were synthesized pursuant to methods of Example 804 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 15.

TABLE 15 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 805 2128 C22 H26 F3 N5 O3 466.0 8.6 30 Example 806 2129 C22 H26 F3 N5 O2 450.1 13.1 37

Example 807 Preparation of (R)-1-(3-Amino-4-chlorobenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2132)

A mixture of (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine (32.6 mg), 10% Pd-activated carbone (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. The Pd catalyst was filtered off, and the filtrate was concentrated. Solid phase extraction (Bond Elut™ SI, 20% methanol/AcOEt) afforded (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl) glycyl}amino]pyrrolidine (Compound No. 2132) (10.5 mg, 34%): The purity was determined by RPLC/MS (84%); ESI/MS m/e 470.2 (M⁺+H, C₂₁H₂₃ClF₃N₅O₂).

Example 808 Preparation of (R)-1-(2-Amino-4,5-methylenedioxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine

To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4,5-methylenedioxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH₃CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH. Product was eluted off using 2 N NH₃ in CH₃OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine.

A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine prepared above, 10% Pd-activated carbone (22 mg), and methanol (3.0 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The Pd catalyst was filtered off, and the filtrate was concentrated to afford (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (87.1 mg, quant.): Any remarkable by-products were not detected in TLC.

(R)-1-(3-Amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine and (R)-1-(3-amino-4-methylbenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine were also synthesized pursuant to methods of Example 808 using the corresponding reactant respectively.

(R)-1-(3-Amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine: 101 mg, quant.; Any remarkable by-products were not detected in TLC.

(R)-1-(3-amino-4-methylbenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine: 97.2 mg, quant.; Any remarkable by-products were not detected in TLC.

Example 809 Preparation of (R)-1-(3-Amino-4-chlorobenzyl)-3-[{N-2-(text-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine

To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH₃CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH. Product was eluted off using 2 N NH in CH₃OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.

A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine prepared above, 10% Pd-activated carbone (22 mg), ethyl acetate (2.7 ml) and methanol (0.3 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. The Pd catalyst was filtered off, and the filtrate was concentrated to afford (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (89.7 mg, quant.): Any remarkable by-products were not detected in TLC.

Example 810 Preparation of (R)-1-(3-Amino-4-hydroxybenzyl)3-[{N-(2Amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2187)

A solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (20 mg), prepared pursuant to methods of Example 808, in 4 N HCl in dioxane (2.0 mL) was stirred at room temperature overnight. After the solution was concentrated, the residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH₃OH, and eluted off using 2 N NH in CH₃OH. Concentration and preparative TLC (SiO₂, AcOEt/MeOH=4:1) afforded (R)-1-(3-amino-4-hydroxybenzyl)3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2187) (9.6 mg, 59%): The purity was determined by RPLC/MS (86%); ESI/MS m/e 452.3 (M⁺+H, C₂₁H₂₄F₃N₅O₃).

Example 811 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-{4-chloro-3-(dimethylamino)benzyl}pyrrolidine (Compound No. 2133)

To a mixture of (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (44.9 mg), methanol (0.95 mL), aceticacid (0.05 mL), and 37% aqueous HCHO solution (0.15 mL) was added NaBH₃CN (38 mg). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and evaporated. To the residue was added 2 N aqueous NaOH solution and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated, and the residue was loaded onto Varian™ SCX column and washed with CH₃OH. Product was eluted off using 2 N NH₃ in CH₃OH and concentrated. The residue was dissolved in 50% conc. HCl/dioxane and the solution was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 10 with 5 N aqueous NaOH solution and extracted with ethyl acetate (2 times). The combined extracts were dried over Na₂SO₄, filtered, and evaporated. Preparative TLC (SiO₂, 20% MeOH/AcOEt) gave (R)3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-{4-chloro-3-(dimethylamino)benzyl)pyrrolidine (Compound No. 2133). (10.9 mg, 28%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 498.3 (M⁺+H, C₂₃H₂₅ClF₃N₅O₂).

Examples 812-814

The compounds of this invention were synthesized pursuant to methods of Example 811 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 16.

TABLE 16 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 812 2134 C₂₄H₂₈F₃N₅O₄ 508.4 19.0 50 Example 813 2135 C₂₄H₃₀F₃N₅O₃ 494.4 21.8 50 Example 814 2136 C₂₄H₃₀F₃N₅O₂ 478.4 29.2 69

Example 815 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(3-methylamino-4-hydroxybenzyl)pyrrolidine (Compound No. 2158)

To a mixture of (R)-1-(3-amino-4-hydroxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (27.3 mg, 0.049 mmol), 37% HCHO solution (4.0 mg, 0.049 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH₃CN (9.2 mg) in methanol (0.2 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (8 mL) and concentrated.

The resulting material was dissolved in methanol (1 mL) and 4 N HCl in dioxane (1.0 mL) was added. The solution was stirred at room temperature for 3 h. After the solution was concentrated, the residue was dissolved in methanol (1 mL), loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH₃ in CH₃OH (8 mL). Concentration and preparative TLC (SiO₂) afforded (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(3-methylamino-4-hydroxybenzyl)pyrrolidine (Compound No. 2158) (4.3 mg, 19%): The purity was determined by RPLC/MS (71%); ESI/MS m/e 480.3 (M⁻+H, C₂₂H₂₆F₃N₅O₃).

Example 816 Preparation of (R)-1-(3-Acetylamino-4-methoxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2152)

To a solution of (R)-1-(3-amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (50.5 mg)in pyridine (1 mL) was added acetic anhydride (1 mL). The reaction mixture was stirred at room temperature overnight and methanol was added. The mixture was evaporated, and 1 N NaOH solution was added. The mixture was extracted with ethyl acetate and the organic layer was concentrated. Preparative TLC gave (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine.

The resulting (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine was dissolved in 50% 6 N hydrochloric acid in dioxane and the solution was stirred at room temperature for 2 h. The mixture was adjusted to pH 10 with 5 M NaOH solution, and extracted with ethyl acetate. The organic layer was evaporated and preparative TLC (SiO., AcOEt/MeOH=4:1) afforded (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2152) (3.7 mg, 8%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 508.3 (M⁺+H, C₂₄H₂₈F₃N₅O₄).

Examples 817-819

The compounds of this invention were synthesized pursuant to methods of Example 816 using the corresponding reactants respectively. The ESI/MS data and yields are summarized in Table 17.

TABLE 17 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 817 2150 C23H25ClF3N5O3 512.3 3.8  9 Example 818 2151 C24H26F3N5O5 522.2 3.1  8 Example 819 2153 C24H28F3N5O3 492.3 4.3 10

Example 820 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(benz[d]oxazol-5-yl)pyrrolidine (Compound No. 2189).

A solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (20 mg), prepared pursuant to methods of Example 808, in THF (2 mL) was treated with triethyl orthoformate (0.020 mL, 3.3 eq) and pyridiniump-toluenesulphonate (1.2 mg, 0.4 eq). The reaction mixture was stirred overnight under reflux. After cooling to room temperature, the mixture was concentrated. The residue was dissolved in AcOEt, loaded onto BondElu™ Si column, eluted off using ethyl acetate/methanol=4/1, and concentrated.

The resulting material was dissolved into AcOEt (1.5 mL), and 4 N HCl in dioxane (0.5 mL) was added. The solution was stirred at room temperature overnight, adjusted to pH 10 with 5 M NaOH aqueous solution, and extracted with AcOEt. The extract was concentrated and purified by PTLC (SiOr, AcOEt/MeOH=4:1) to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(benz[d]oxazol-5-yl)pyrrolidine (Compound No. 2189) (0.5 mg, 3%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 462.3 (M⁺+H, C₂₂H₂₂F₃N₅O₃).

Example 821 Preparation of (R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(benzo[c]thiadiazol-5-yl)pyrrolidine (Compound No. 2183)

To a mixture of 5-(hydroxymethyl)benzo[c]thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl)polystyrene (86 mg), and chloroform (1 mL) was added methanesulfonyl chloride (0.0042 mL) and the mixture was stirred at room temperature for 1.5 h. Acetonitrile (1 mL) and (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.060 mmol) was added and the reaction mixture was stirred at 50° C. for 3 h. After cooling to room temperature, phenyl isocyanate (30 mg) was added, and the mixture was stirred at room temperature for 1 h, loaded onto Varian™ SCX column and washed with CH₃OH (5 mL) and CHCl₃ (5 mL). Product was eluted using 2 N NH₃ in CH₃OH (3 mL) and concentrated.

The resulting material was dissolved into dichloromethane (1 mL), and 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane (1 mL) was added. The solution was stirred at room temperature for 5 h, loaded onto Varian™ SCX column and washed with CH₃OH and dichloromethane. Product was eluted using 2 N NH₃ in CH₃OH and concentrated. Preparative TLC (SiO₂, AcOEt/MeOH=3:1) afforded (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(benzo[c]thiadiazol-5-yl)pyrrolidine (Compound No. 2183) (11.5 mg, 48%): The purity was determined by RPLC/MS (86%); ESI/MS m/e 479.2 (M⁺+H, C₂₁H₂₁F₃N₆O₂S).

Reference Example 6 Preparation of 4-[{N-(1-(9-fuluorenylmethoxycarbonyl) pyrrolidin-3-yl) carbamoylmethyl}aminomethyl]-3-methoxyphenyloxymethyl-polystyrene

To a solution of (R)-1-(9-fuluorenylmethoxycarbonyl)-3-glycylamino-pyrrolidine hydrochloride (4.38 g, 10 mmol) in DMF (65 mL) were added acetic acid (0.3 mL), sodium triacetoxyborohydride (1.92 g), and 4-formyl-3-(methoxyphenyloxymethyl)-polystyrene (1 mmol/g, 200 g). The mixture was shaken for 2 h and filtered. The resin was washed with MeOH, DMF, CH₂Cl₂, and methanol, and dried to afford the desired material (2.73 g).

Examples 822-912 General Procedure for Solid-Phase Synthesis of 3-Aminopyrrolidines

To a mixture of the corresponding acid (1.6 mmol), HBTU (1.6 mmol), and DMF (6 mL) was added diisopropylethylamine (3.6 mmol), and the mixture was shaken for 2 min. 4-[{N-(1-(9-fuluorenylmethoxycarbonyl)pyrrolidin-3-yl) carbamoylmethyl}aminomethyl]-3-methoxyphenyloxymethyl-polystyrene (400 mg, 0.4 mmol) was added and the mixture was shaken for 1 h and filtered. The resin was rinsed with DMF and CH₂Cl₂, and dried.

A mixture of the resulting resin, piperidine (3.2 mL), and DMF (12.8 mL) was shaken for 10 min and filtered. The resin was washed with DMF and CH₂Cl₂, and dried.

To the dry resin (0.05 mmol) was added a mixture of NaBH(OAc)₃ (0.25 mmol), AcOH (0.025 mL) and DMF (1 mL) The corresponding aldehyde (2.5 mmol) was added, and the mixture was shaken for 2 h, then filtered and washed with CH₃OH, 10% diisopropylethylamine in DMF, DMF, CH₂Cl₂, and CH₃OH. A mixture of the resin, water (0.050 mL), and trifluoroacetic acid (0.95 mL) was shaken for 1 h and filtered. The resin was washed with CH₂Cl₂ and CH₃OH. The filtrate and washings were combined and concentrated. The crude material was loaded onto Varian™ SCX column and washed with CH₃OH (15 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. Preparative TLC or HPLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 18.

TABLE 18 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 822 1805 C21 H21 Br F3 N3 O2 S 516 13.3 76 Example 823 1806 C22 H24 F3 N3 O3 S 468 12.8 81 Example 824 1807 C22 H24 F3 N3 O4 S 484 13.7 83 Example 825 1808 C22 H24 F3 N3 O4 S 484 14.9 91 Example 826 1809 C21 H22 F3 N3 O3 S 454 12.9 84 Example 827 1810 C22 H22 F3 N3 O4 S 482 12.9 79 Example 828 1811 C24 H26 F3 N3 O2 S 478 12.9 79 Example 829 1812 C22 H24 F3 N3 O2 S2 484 5.3 32 Example 830 1813 C23 H26 F3 N3 O2 S 466 12.8 81 Example 831 1814 C23 H24 F3 N3 O3 S 480 9.7 59 Example 832 1815 C23 H26 F3 N3 O2 S 466 12.7 80 Example 833 1816 C24 H28 F3 N3 O2 S 480 14.4 88 Example 834 1817 C25 H30 F3 N3 O2 S 494 14.1 84 Example 835 1818 C21 H22 Br F2 N3 O3 482 13.4 82 Example 836 1819 C22 H25 F2 N3 O4 434 11.7 79 Example 837 1820 C22 H25 F2 N3 O5 450 11.8 77 Example 838 1821 C22 H25 F2 N3 O5 450 13.3 87 Example 839 1822 C21 H23 F2 N3 O4 420 11.9 83 Example 840 1823 C22 H23 F2 N3 O5 448 11.9 78 Example 841 1824 C24 H27 F2 N3 O3 444 9.1 60 Example 842 1825 C22 H25 F2 N3 O3 S 450 11.3 74 Example 843 1826 C23 H27 F2 N3 O3 432 10.8 74 Example 844 1827 C23 H25 F2 N3 O4 446 12.7 84 Example 845 1828 C23 H27 F2 N3 O3 432 11.7 80 Example 846 1829 C24 H29 F2 N3 O3 446 14.3 94 Example 847 1830 C24 H29 F2 N3 O3 446 10.0 66 Example 848 1831 C22 H28 Br N3 O3 462 4.8 31 Example 849 1832 C23 H31 N3 O4 414 10.4 74 Example 850 1833 C23 H31 N3 O5 430 12.1 83 Example 851 1834 C23 H31 N3 O5 430 12.0 82 Example 852 1835 C22 H29 N3 O4 400 7.9 58 Example 853 1836 C23 H29 N3 O5 428 11.1 76 Example 854 1837 C25 H33 N3 O3 424 13.3 92 Example 855 1838 C23 H31 N3 O3 S 430 8.7 60 Example 856 1839 C24 H33 N3 O3 412 11.3 81 Example 857 1840 C24 H31 N3 O4 426 12.9 89 Example 858 1841 C24 H33 N3 O3 413 12.8 91 Example 859 1842 C25 H35 N3 O3 426 8.7 60 Example 860 1843 C25 H35 N3 O3 426 12.2 84 Example 861 1844 C26 H37 N3 O3 440 11.3 76 Example 862 1845 C31 H37 Br N4 O2 577 6.4 30 Example 863 1846 C23 H28 F3 N3 O2 S 480 12.8 81 Example 864 1847 C25 H31 F2 N3 O3 460 12.2 78 Example 865 1848 C27 H29 N3 O4 460 6.1 39 Example 866 1849 C29 H31 N3 O2 454 15.1 98 Example 867 1850 C28 H31 N3 O2 442 12.7 85 Example 868 1851 C28 H31 N3 O2 442 14.3 95 Example 869 1852 C28 H29 N3 O3 456 3.4 22 Example 870 1853 C27 H29 N3 O6 S 524 15.4 87 Example 871 1854 C29 H31 N3 O4 S 518 15.8 90 Example 872 1855 C28 H31 N3 O4 S 506 17.0 99 Example 873 1856 C28 H31 N3 O4 S 506 3.0 17 Example 874 1857 C28 H29 N3 O5 S 520 10.0 57 Example 875 1858 C20 H22 Br2 N4 O2 511 9.3* 37 Example 876 1859 C21 H25 Br N4 O3 461 6.7* 29 Example 877 1860 C21 H25 Br N4 O4 477 9.5* 40 Example 878 1861 C21 H25 Br N4 O4 477 10.0* 42 Example 879 1862 C20 H23 Br N4 O3 447 7.8* 34 Example 880 1863 C21 H23 Br N4 O4 475 3.4* 14 Example 881 1864 C21 H25 Br N4 O2 S 477 3.9* 16 Example 882 1865 C22 H25 Br N4 O3 473 6.4* 27 Example 883 1866 C23 H29 Br N4 O2 472 7.0* 29 Example 884 1867 C23 H29 Br N4 O2 473 7.6* 32 Example 885 1868 C24 H31 Br N4 O2 487 9.1* 37 Example 886 1869 C20 H22 Br I N4 O2 557 8.9* 33 Example 887 1870 C21 H25 I N4 O3 509 9.2* 37 Example 888 1871 C21 H25 I N4 O4 525 6.3* 25 Example 889 1872 C21 H25 I N4 O4 525 5.9* 23 Example 890 1873 C20 H23 I N4 O3 495 7.7* 31 Example 891 1874 C21 H23 I N4 O4 523 8.2* 32 Example 892 1875 C23 H27 I N4 O2 519 6.7* 26 Example 893 1876 C21 H25 I N4 O2 525 4.3* 17 Example 894 1877 C22 H27 I N4 O2 507 7.9* 32 Example 895 1878 C22 H25 I N4 O3 521 8.4* 33 Example 896 1879 C23 H29 I N4 O2 521 8.2* 32 Example 897 1880 C23 H29 I N4 O2 521 8.1* 32 Example 898 1881 C24 H31 I N4 O2 535 8.6* 33 Example 899 1882 C20 H22 Br N5 O4 476 5.3* 22 Example 900 1883 C21 H25 N5 O5 428 5.7* 26 Example 901 1884 C21 H25 N5 O6 444 8.2* 36 Example 902 1885 C21 H25 N5 O6 444 5.0* 22 Example 903 1886 C20 H23 N5 O5 414 8.7* 40 Example 904 1887 C21 H23 N5 O6 442 7.8* 34 Example 905 1888 C23 H27 N5 O4 438 5.6* 25 Example 906 1889 C21 H25 N5 O4 S 444 13.2* 58 Example 907 1890 C22 H27 N5 O4 426 11.3* 51 Example 908 1891 C22 H25 N5 O5 440 7.4* 33 Example 909 1892 C22 H27 N5 O4 426 5.5* 25 Example 910 1893 C23 H29 N5 O4 440 5.7* 25 Example 911 1894 C23 H29 N5 O4 440 9.4* 41 Example 912 1895 C24 H31 N5 O4 455 8.5* 37 *Yield of TFA salt.

Reference Example 7 Preparation of 2-Carbamoyl-1-(4-chlorobenzyl)pyrrolidine

A solution of dl-prolinamide hydrochloride (2.5 g, 21.8 mmol) in CH₃CN (35 mL) was treated with Et₃N (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol). The reaction mixture was stirred at 70° C. for 4 h and then at 25° C. for 16 h. The resulting mixture was diluted with CH₂Cl₂ (20 mL) and was washed with water(3×30 mL). The organic phase was dried (MgSO₄) and concentrated. Chromatography (SiO₂, 1% CH₃OH—CH₂Cl₂) afforded 2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine (5.21 g, 81%).

Reference Example 8 Preparation of 2-(Aminomethyl)-1-(4-chlorobenzyl)pyrrolidine

2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine was dissolved in 1M BH₃-THF (9.4 mL) and heated to 70° C. After 16 h and 25 h, additional 0.5 equiv. of 1M BH₃-THF were added. After 40 h, 1 N aqueous HCl solution (14 mL) was added and the reaction was heated to reflux for 3 h, 3 N aqueous HCl solution (6 mL) was added and the reaction was heated for an additional 3 h. The reaction mixture was cooled to 25° C., basicified with 4 N aqueous NaOH solution and extracted with CH₂Cl₂ (4×15 mL). Chromatography (SiO:, 8:1:1 ⁻PrOH—H O—NH₄OH) afforded 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (1.21 g, 86%).

Optically active (S)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine and (R)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine were also prepared pursuant to the above method using the corresponding reactant respectively.

(S)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine: ₁H NMR (CDCl₃, 400 MHz) δ 1.40-1.80 (m, 5 H), 1.80-1.95 (m, 1 H), 2.12-2.21 (m, 1 H), 2.48-2.65 (m, 1 H), 2.66-2.78 (m, 2 H), 2.85-2.95 (m, 1 H), 3.26 (d, J=13.2 Hz, 1 H), 3.93 (d, J=13.2 Hz, 1 H), 7.20-7.40 (m, 4 H).

(R)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine showed the same ¹H NMR with that of (S)−isomer.

Example 913 Preparation of 2-{(N-benzoylleucyl)aminomethyl}-1-(4-chlorobenzyl)pyrrolidine (Compound No. 344)

A solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mmol) in CHCl₃ (1 mL) was treated with EDCI (23 mg), HOBt (16.2 mg) and Et₃N (15.2 μL), and stirred at 25° C. for 16 h. The reaction mixture was diluted with CH₂Cl₂ (0.5 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL), dried by filtration through a PTFE membrane and concentrated to afford 2-((N-benzoylleucyl)aminomethyl}-1-(4-chlorobenzyl)pyrrolidine (compound No. 344) (74 mg, quant): The purity was determined by RPLC/MS (85%); ESI/MS m/e 442 (M⁺+H, C₂₅H₃₂ClN₃O₂).

Examples 914-935

The compounds of this invention were synthesized pursuant to methods of Example 913 using the corresponding reactant respectively. Chromatography, if needed, (HPLC-C₁₈, CH₃CN/H₂O/TFA) afforded the desired material as the TFA salt. The ESI/MS data and yields are summarized in Table 19 and compound No. 339 and 340 showed the following ₁H NMR spectra respectively.

TABLE 19 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 914 330 C21 H24 Cl N3 O2 386  75* quant Example 915 331 C22 H26 Cl N3 O2 400  44* 70 Example 916 332 C24 H30 Cl N3 O5 476 57 quant Example 917 333 C20 H23 Cl N4 O2 387 40 quant Example 918 334 C22 H26 Cl N3 O2 400 68 quant Example 919 335 C21 H23 Cl N4 O4 431 73 quant Example 920 336 C22 H23 Cl F3 N3 O2 454 75 quant Example 921 337 C22 H26 Cl N3 O2 400 68 quant Example 922 338 C22 H26 Cl N3 O2 400 70 quant Example 923 341 C22 H26 Cl N3 O2 400  80* quant Example 924 342 C22 H26 Cl N3 O2 400 68 quant Example 925 343 C24 H30 Cl N3 O2 428 63 quant Example 926 345 C23 H27 Cl N2 O2 399  68* quant Example 927 346 C23 H26 Cl F N2 O3 433 51 quant Example 928 347 C24 H29 Cl N2 O2 413 47 quant Example 929 348 C23 H27 Cl N2 O2 399 26 quant Example 930 349 C21 H25 Cl N2 O3 S 421 42 quant Example 931 350 C26 H33 Cl N2 O3 457   12.4 54 Example 932 351 C22 H26 Cl N3 O3 416 34 81 Example 933 352 C22 H25 Cl2 N3 O3 450 51 quant *Yield of TFA salt.

Example 934

Compound No. 339: 82%; ₁H NMR (CDCl₃) δ 1.52-1.75(m, 4 H), 1.84-1.95 (m, 1 H), 2.10-2.20 (m, 1 H), 2.67-2.78 (m, 1 H), 2.80-2.90 (m, 1 H), 3.10-3.20 (m, 1 H), 3.25 (d, J=13.1 Hz, 1 H), 3.50-3.60 (m, 1 H), 3.89 (d, J=13.1 Hz, 1 H), 4.28-4.20 (m, 2 H), 7.00-7.05 (m, 1 H), 7.12-7.29 (m, 4 H), 7.51 (t, J=7.8 Hz, 1 H), 7.74 (d, J=7.8 Hz, 1 H), 7.99 (d, J=7.8 Hz, 1 H), 8.10-8.27 (m, 2 H).

Example 935

Compound No. 340: 68%; ₁H NMR (CDCl) δ 1.55-1.73(m, 4 H), 1.86-1.97 (m, 1 H), 2.12-2.21 (m, 1 H), 2.67-2.76 (m, 1 H), 2.86-2.93 (m, 1 H), 3.14-3.21 (m, 1 H), 3.27 (d, J=13.1 Hz, 1 H), 3.52-3.59 (m, 1 H), 3.89 (d, J=13.1 Hz, 1 H), 4.09-4.21 (m, 2 H), 7.00-7.07 (m, 1 H), 7.12-7.30 (m, 4 H), 7.50 (t, J=7.8 Hz, 1 H), 7.73 (d, J=7.8 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H), 8.10-8.25 (m, 2 H).

Reference Example 9 Preparation of 3-(Aminomethyl)-1-(4-chlorobenzyl)pyrrolidine

To a mixture of 4-carboxy-1-(4-chlorobenzyl)pyrrolidin-2-one (5.05 g, 20 mmol), EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane (100 mL) was added 0.5 Mammonia in dioxane (60 mL, 30 mmol). The reaction mixture was stirred at room temperature for 15 h and washed with 2 N HCl (3 times) and 2 N NaOH aqueous solution (100 mL×4). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g) as a colorless solid.

To a solution of 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.45 g) in THF (15 mL) was added 1.0 N BH₃ in THF (25 mL). The reaction mixture was stirred at 65° C. for 15 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (30 mL) and conc. HCl (10 mL) were added and the mixture was stirred at 100° C. for 2 h and room temperature for 1 h. 2 N NaOH aqueous solution (100 mL) was added and the mixture was extracted with AcOEt (50 mL×3). The combined organic layers were dried over K₂CO₃, filtered and concentrated. Column chromatography (SiO₂, 15% CH₃OH—5% Et₃N in CH₂Cl₂) afforded 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 19%) as a colorless oil.

Reference Example 10 Preparation of 1-(4-Chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine

A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol), Et₃N (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg), and dichloromethane (20 mL) was stirred at room temperature for 15 h. Dichloromethane (50 mL) was added and the solution was washed with 2 N NaOH solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).

To a solution of 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (804 mg, 2.11 mmol) in methanol (10 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and 1 N NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodiumsulfate and concentrated to give desired 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (599 mg, 100%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 282.2 (M⁺+H, C₁₄H₂₀(ClN₃O).

Example 936 Preparation of 3-[{N-(3-Trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1463)

A solution of 3-(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (0.2 mL) was added to a mixture of 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (0.050 mmol) and piperidinomethylpolystyrene (60 mg) in chloroform (0.2 mL) and dichloromethane (1 mL). After the reaction mixture was stirred at room temperature for 2.5 h, methanol (0.30 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH₃OH (15 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford (3-[{N-3-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(4-chorobenzyl)pyrrolidine (Compound No. 1463) (22.4 mg, 99%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 454.2 (M⁻+H, C₂₂H₂₃ClF₃O₂).

Examples 937-944

The compounds of this invention were synthesized pursuant to methods of Example 936 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 20.

TABLE 20 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 937 1464 C22 H23 Cl F3 N3 O3 470.0 21.0 89 Example 938 1465 C23 H22 Cl F6 N3 O2 522.0 24.5 94 Example 939 1466 C21 H23 Br Cl N3 O2 466.0 20.8 90 Example 940 1467 C21 H23 Cl2 N3 O2 420.0 19.6 93 Example 941 1468 C21 H23 Cl N4 O4 431.2 19.5 91 Example 942 1469 C22 H22 Cl F4 N3 O2 472.0 21.8 92 Example 943 1470 C21 H22 Cl3 N3 O2 456.0 22.1 97 Example 944 1471 C21 H22 Cl F2 N3 O2 422.0 20.9 99

Example 945 Preparation of 3-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1506)

A solution of 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (0.050 mmol) in CHCl₃ (1.35 mL) and tert-butanol (0.05 mL) was treated with 2-amino-4,5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 19 h. The mixture was loaded onto Varian™ SCX column, and washed with CH₃OH/CDCl₃ 1:1 (10 mL) and CH₃OH (10 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 3-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1506) (22.0 mg, quant): The purity was determined by RPLC/MS (92%); ESI/MS m/e 437 (C₂₁H₂₃ClF₂N₄O₂).

Examples 946-952

The compounds of this invention were synthesized pursuant to methods of Example 945 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 21.

TABLE 21 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 946 1506 C21 24 Br Cl N4 O2 481 20.6 86 Example 947 1507 C21 H24 F Cl N4 O2 419 21.7 quant Example 948 1509 C27 H28 Cl N3 O2 462 26.5 quant Example 949 1510 C21 H24 Cl I N4 O2 527 22.0 84 Example 950 1511 C19 H21 Br Cl N3 O2 S 472 23.7 quant Example 951 1512 C21 H24 Cl2 N4 O2 435 22.3 quant Example 952 1513 C27 H28 Cl N3 O4 S 526 24.6 94

Reference Example 11 Preparation of 1-(4-Chlorobenzyl)nipecotic acid

4-chlorobenzyl chloride (6.42 g, 39.9 mmol) and ¹Pr₂NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH₃CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO₃ (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO₃ and brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M⁺+H, C₁₅H₂₁ClNO₂).

A solution of LiOH (1.66 g) in H₂O (25 mL) was added to the solution of ethyl 1-(4-chlorobenzyl)nipecotate in THF (60 mL) and CH₃OH (20 mL). The reaction mixture was stirred at room temperature for 15 h. The solvent was removed under reduced pressure to afford an amorphous solid which was purified by column chromatography (SiO₂, 50% CH₃OH—CH₂Cl₂) to yield-1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as a pale yellow amorphous solid. The purity was determined by RPLC/MS (>95%); ESI/MS m/e 254.0 (M⁺+H, C₁₃H₁₇ClNO₂).

Reference Example 12 Preparation of 1-(4-Chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine

A solution of 1-(4-chlorobenzyl)nipecotic acid (7.06 g, 27.8 mmol) in ^(t)BuOH (500 mL) was treated with Et₃N (3.38 g) and activated 3 A molecular sieves (30 g). Diphenylphosphoryl azide (8.58 g) was added, and the reaction mixture was warmed at reflux for 18 h. The mixture was cooled and the solvent was reflux for 18 h. The mixture was cooled and the solvent was remove under vacuum. The residue was dissolved in EtOAc (500 mL), and the organic phase was washed with saturated aqueous NaHCO₃ (2×100 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated in vacuo. Chromatography (SiO₂, 25% EtOAc-hexane) afforded 1-(4-chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine (2.95 g, 32.6%) as a white crystalline solid: ¹H NMR (CDCl₃, 300 MHz) δ 1.4-1.75 (br, 4 H), 2.2-2.7 (br, 4 H), 3.5 (br, 2 H), 3.8 (br, 1 H), 7.3 (br, 4 H); The purity was determined by RPLC/MS (>99%); ESI/MS m/e 269.2 (M⁺+H-56, C₁₇H₂₆ClN₂O₂).

Reference Example 13 Preparation of 3-Amino-1-(4-chlorobenzyl)piperidine

A solution of 1-(4-chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine (2.55 g, 7.85 mmol) in CH₂OH (25 mL) was treated with 1 N HCl-Et₂O (50 mL). The reaction mixture was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford 3-amino-l-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quant).

The purity was determined by RPLC/MS (>95%),; ESI/MS m/e 225.2 (M⁺+H, C₁₂H₁₈ClN₂).

Example 953 Preparation of 1-(4-Chlorobenzyl)-3-[{N-(3-methylbenzoyl)glycyl}amino]piperidine (Compound No. 355).

N-(3-Methylbenzoyl)glycine (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 mg) were added to a solution of 1-(4-chlorobenzyl)-3-aminopiperidine dihydrochloride (14.9 mg, 0.050 mmol) and Et₃N (15.2 mg) in CHCl₃ (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-3-[{N-(3-methylbenzoyl)glycyl}amino]piperidine (compound No. 355) as a pale yellow oil (17.4 mg, 87%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 400.0 (M⁺+H, C₂₂H₂₆ClN₃O₂).

Examples 954-982.

The compounds of this invention were synthesized pursuant to methods of Example 953 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 22 and compound No. 358 showed the following ¹H NMR spectra.

TABLE 22 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 954 354 C21 H24 Cl N3 O2 386 16.1 83 Example 955 356 C20 H23 Cl N4 O2 387 19.4 100  Example 956 357 C22 H26 Cl N3 O2 400 16.8 84 Example 957 359 C22 H26 Cl N3 O2 400 8.9 17 Example 958 360 C22 H25 Cl N4 O4 445 25.6 quant Example 959 361 C23 H27 Cl N2 O2 399 15.5 29 Example 960 362 C24 H29 Cl N2 O3 429 12.4 58 Example 961 363 C21 H25 Cl N2 O2 S 405 22.2 quant Example 962 364 C24 H29 Cl N2 O4 445 20.7 93 Example 963 365 C24 H29 Cl N2 O2 413 15.6 75 Example 964 366 C23 H26 Cl F N2 O3 433 21.6 100  Example 965 367 C23 H27 Cl N2 O2 399 11.9 60 Example 966 368 C22 H25 Cl N2 O2 385 16.0 83 Example 967 369 C22 H24 Cl2 N2 O2 419 13.9 60 Example 968 370 C26 H33 Cl N2 O3 457 15.9 54 Example 969 371 C25 H31 Cl N2 O3 443 19.6 84 Example 970 372 C21 H25 Cl N2 O3 S 421 23.0 quant Example 971 373 C23 H28 Cl N3 O2 414 19.1 92 Example 972 374 C24 H30 Cl N3 O3 444 18.6 84 Example 973 375 C23 H27 Cl2 N3 O2 448 18.0 80 Example 974 376 C24 H30 Cl N3 O3 444 19.6 88 Example 975 377 C25 H31 Cl2 N3 O2 476 20.7 87 Example 976 378 C27 H33 Cl F N3 O2 486 23.9 98 Example 977 379 C25 H30 Cl N3 O3 456 33.3 quant Example 978 380 C24 H30 Cl N3 O2 428 9.8 46 Example 979 381 C21 H26 Cl N3 O3 S 436 10.3 47 Example 980 382 C22 H26 Cl N3 O3 416 24.4 quant Example 981 383 C22 H25 Cl2 N3 O3 450 27.5 quant

Example 982

Compound No. 358: 88%; ¹H NMR (CDCl₃) δ 1.53-1.75(m, 4 H), 2.12-2.20 (m, 1 H), 2.37-2.50 (m, 2 H), 2.53-2.61 (m, 1 H), 3.38-3.50 (m, 2 H), 2.53-2.61 (m, 1 H), 3.38-3.50 (m, 2 H), 4.06-4.20 (m, 3 H), 7.10-7.13 (m, 1H), 7.18-7.30 (m, 4 H), 7.59 (t, J=7.8 Hz, 1 H), 7.79 (d, J=7.8 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H), 8.11 (s, 1 H).

Reference Example 14 Preparation of 1-benzyl-4-[{N-(tert-butoxycarbonyl)glycyl}amino]piperidine

A solution of 4-amino-1-benzylpiperidine (3.80 g, 20 mmol) in CH₂Cl₂ (40 mL) was treatedwith N-(tert-butoxycarbonyl)glycine (3.48 g, 20 mmol), EDCI (4.02 g, 21 mmol) and HOBt (2.83 g, 21 mmol). After the reaction mixture was stirred at room temperature for 12 h, 2 N NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, ethyl acetate/MeOH/Et₃N=85/12/3) afforded 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g, 95%).

Reference Example 15 Preparation of 1-(4-Chlorobenzyl)-4-(glycylamino)piperidine

To a solution of 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g) in methanol (80 mL) was added 4 N HCl in dioxane (19 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO₂, AcOEt/MeOH/Et₃N=85/12/3) gave 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (3.91 g, 83%): ¹H NMR (CDCl₃, 400 MHz) d 1.47-1.59 (m, 2 H), 1.59 (br, 2 H), 1.76-1.96 (m, 2 H), 2.10-2.19 (m, 2 H), 2.75-2.87 (m, 2 H), 3.29 (s, 2 H), 3.50 (s, 2 H), 3.65-3.89 (m, 1 H), 7.15-7.23 (m, 1 H), 7.23-7.33 (m, 5 H).

Other 4-acylamino-1-benzylpiperidines were also synthesized pursuant to methods of Reference Example 13 and 14 using the corresponding reactant respectively.

4-(β-alanylamino)-1-benzylpiperidine: 2.46 g, 51% (2 steps).

1-benzyl-4-((S)-leucylamino)piperidine: 1.78 g, 74% (2 steps).

1-benzyl-4-((R)-leucylamino)piperidine: 1.48 g, 61% (2 steps).

Example 983 Preparation of 4-(N-benzoylglycyl)amino-1-benzylpiperidine (Compound No. 386)

A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give 4-(N-benzoylglycyl)amino-1-benzylpiperidine (compound No. 386) (11.3 mg, 64%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 352.0 (M⁺+H, C₂₁H₂₅N₃O₂).

Examples 984-1034

The compounds of this invention were synthesized pursuant to methods of Example 983 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 23.

TABLE 23 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 984 384 C22 H26 Cl N3 O2 400 60.0 quant Example 985 385 C21 H23 Cl N4 O4 431 58.7 91 Example 986 387 C25 H27 N3 O2 402.5 15.5 77 Example 987 388 C21 H24 N4 O4 397.0 16.2 82 Example 988 389 C23 H27 N3 O4 410.0 16.2 79 Example 989 390 C22 H24 F3 N3 O2 420.0 17.4 83 Example 990 391 C22 H23 F4 N3 O2 438.0 18.4 84 Example 991 392 C22 H24 F3 N3 O3 436.0 17.1 79 Example 992 393 C21 H24 Br N3 O2 430.0 18.0 84 Example 993 394 C21 H24 Cl N3 O2 386.0 16.4 85 Example 994 395 C21 H24 Br N3 O2 430.0 17.2 80 Example 995 396 C21 H23 F2 N3 O2 388.0 15.1 78 Example 996 397 C21 H23 Cl2 N3 O2 420.0 11.7 56 Example 997 398 C22 H27 N3 O2 366.0 13.1 72 Example 998 399 C26 H29 N3 O2 416.0 15.8 76 Example 999 400 C22 H26 N4 O4 411.0 17.4 85 Example 1000 401 C24 H29 N3 O4 424.0 16.9 80 Example 1001 402 C23 H26 F3 N3 O2 434.0 17.7 82 Example 1002 403 C23 H25 F4 N3 O2 452.0 18.6 82 Example 1003 404 C23 H26 F3 N3 O3 450.0 17.8 79 Example 1004 405 C22 H26 Br N3 O2 444.0 17.9 81 Example 1005 406 C22 H26 Cl N3 O2 400.0 15.5 78 Example 1006 407 C22 H26 Er N3 O2 444.0 17.8 80 Example 1007 408 C22 H25 F2 N3 O2 402.0 15.6 78 Example 1008 409 C22 H25 Cl2 N3 O2 434.0 17.6 81 Example 1009 410 C25 H33 N3 O2 408.0 16.2 79 Example 1010 411 C29 H35 N3 O2 458.5 18.8 82 Example 1011 412 C25 H32 N4 O4 453.0 19.4 86 Example 1012 413 C27 H35 N3 O4 466.0 19.8 85 Example 1013 414 C26 H32 F3 N3 O2 476.0 20.2 85 Example 1014 415 C26 H31 F4 N3 O2 494.0 20.5 83 Example 1015 416 C26 H32 F3 N3 O3 492.0 19.5 79 Example 1016 417 C25 H32 Br N3 O2 486.0 19.1 79 Example 1017 418 C25 H32 Cl N3 O2 442.0 17.7 80 Example 1018 419 C25 H32 Br N3 O2 486.0 20.3 83 Example 1019 420 C25 H31 F2 N3 O2 444.0 18.6 84 Example 1020 421 C25 H31 Cl2 N3 O2 476.0 19.4 81 Example 1021 422 C25 H33 N3 O2 408.0 14.4 71 Example 1022 423 C29 H35 N3 O2 458.0 16.4 72 Example 1023 424 C25 H32 N4 O4 453.0 18.1 80 Example 1024 425 C27 H35 N3 O4 466.0 16.4 70 Example 1025 426 C26 H32 F3 N3 O2 476.0 17.3 73 Example 1026 427 C26 H31 F4 N3 O2 494.0 18.8 76 Example 1027 428 C26 H32 F3 N3 O3 492.0 18.4 75 Example 1028 429 C25 H32 Br N3 O2 486.0 17.9 74 Example 1029 430 C25 H32 Cl N3 O2 442.0 15.7 71 Example 1030 431 C25 H32 Br N3 O2 486.0 17.7 73 Example 1031 432 C25 H31 F2 N3 O2 444.0 16.6 75 Example 1032 433 C25 H31 Cl2 N3 O2 476.0 18.7 78 Example 1033 1016  C22 H23 Cl F3 N3 O2 454 32.5* 53 Example 1034 1017  C21 H24 Cl N3 O2 386 55.2* quant *Yield of TFA salt.

Reference Example 16 Preparation of 3-Carbamoyl-1-(4-chlorobenzyl)piperidine

A solution of nipecotamide (6.40 g, 50 mmol) in CH₃CN (150 mL) and ethanol (20 mL) was treated with Et₃N (7.0 mL, 50 mmol) and 4-chlorobenzyl chloride (8.05 g, 50 mmol). The reaction mixture was stirred at 50° C. for 16 h. After cooling to room temperature, saturated aqueous NaHCO₃ (50 mL) and water (150 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL×3) and the combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to give a pale red solid. The crude solid was washed with ether (100 mL) to afford 3-carbamoyl-1-(4-chlorobenzyl)piperidine (6.98 g, 54%).

Reference Example 17 Preparation of 3-(Aminomethyl)-1-(4-chlorobenzyl)piperidine

3-Carbamoyl-1-(4-chlorobenzyl)piperidine (3.80 g, 15 mmol) was dissolved in THF (30 mL) and 1 M BH₃-THF (9.4 mL) was added to the solution. The reaction mixture was stirred at 70° C. for 15 h. After the mixture was cooled to 0° C., 2 N aqueous HCl solution (50 mL) was added and the mixture was stirred at room temperature for additional 3 h, basicified with 4 N aqueous NaOH solution, and extracted with ethyl acetate (100 mL×3). The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. Column chromatography (SiO₂, ethyl acetate/EtOH/Et₃N=80/15/5) afforded 3-(aminomethyl)-1-(4-chlorobenzyl)piperidine (2.05 g, 55%): ¹H NMR (CDCl₃, 400 MHz) δ 1.00-1.09 (m, 1 H), 1.50-1.87 (m, 7 H), 1.97-2.06 (m, 1 H), 2.65-2.77 (m, 2 H), 3.16-3.26 (m, 2 H), 3.32 (s, 2 H), 3.40. (d, J=13.3 Hz, 1 H), 3.49 (d, J=13.3 Hz, 1 H), 7.22-7.33 (m, 5 H).

ExampIe 1035

Preparation of 3-{(N-Benzoylglycyl)amino}methyl-1-(4-chlorobenzyl)piperidine (Compound No. 434)

A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 3-(aminomethyl)-1-(4-chlorobenzyl)piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give 3-((N-benzoylglycyl)amino)methyl-1-(4-chlorobenzyl)piperidine (compound No. 434) (14.7 mg, 74%): The purity was determined by RPLC/MS (91%); ESI/MS m/e 400 (M⁺+H, C₂₂H₂₆ClN₃O₂).

Examples 1036-1058

The compounds of this invention were synthesized pursuant to methods of Example 1035 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 24.

TABLE 24 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1036 435 C26 H25 Cl N3 O2 450 16.0 71 Example 1037 436 C22 H25 Cl N4 O4 445 18.9 85 Example 1038 437 C24 H28 Cl N3 O4 458 18.2 79 Example 1039 438 C23 H25 Cl F3 N3 O2 468 19.0 81 Example 1040 439 C23 H24 Cl F4 N3 O2 486 20.2 83 Example 1041 440 C23 H25 Cl F3 N3 O3 484 18.9 78 Example 1042 441 C22 H25 Br Cl N3 O2 478 19.2 80 Example 1043 442 C22 H25 Cl2 N3 O2 434 17.3 80 Example 1044 443 C22 H25 Br Cl N3 O2 478 18.8 79 Example 1045 444 C22 H24 Cl F2 N3 O2 436 16.7 77 Example 1046 445 C22 H24 Cl3 N3 O2 468 17.9 76 Example 1047 446 C23 H28 Cl N3 O2 414 14.6 71 Example 1048 447 C27 H30 Cl N3 O2 464 17.0 73 Example 1049 448 C23 H27 Cl N4 O4 459 19.5 85 Example 1050 449 C25 H30 Cl N3 O4 472 17.1 72 Example 1051 450 C24 H27 Cl F3 N3 O2 482 19.4 81 Example 1052 451 C24 H26 Cl F4 N3 O2 500 18.2 73 Example 1053 452 C24 H27 Cl F3 N3 O3 498 18.8 76 Example 1054 453 C23 H27 Br Cl N3 O2 492 19.4 79 Example 1055 454 C23 H27 Cl2 N3 O2 448 16.5 74 Example 1056 455 C23 H27 Br Cl N3 O2 492 19.3 78 Example 1057 456 C23 H26 Cl F2 N3 O2 450 17.1 76 Example 1058 457 C23 H26 Cl3 N3 O2 482 16.9 70

Reference Example 18 Preparation of 4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine

A solution of 4-(aminomethyl)piperidine (7.00 g, 61.3 mmol) in CH₃CN (100 mL) was treated sequentially with K₂CO₃ (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol). The reaction mixture was heated to 60° C. for 16 h, cooled to 25° C. and concentrated. The residue was partitioned between CH₂Cl₂ (75 mL) and water (50 mL), and was washed with water (2×50 mL) and brine (1×50 mL). The organic phase was dried (MgSO₄) and concentrated. Chromatography (SiO₂, 4% H₂O—^(i)PrOH) afforded 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (3.58 g, 69%).

Example 1059 Preparation of 4-{(N-Benzoylglycyl)amino}methyl-1-(4-chlorobenzyl)piperidine (Compound No. 458)

A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol) in CH₂Cl₂ (1 mL) was treated with hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et₃N (38 μL, 0.27 mmol). The reaction mixture was stirred for 16 h at 25° C., diluted with 1 mL of CH₂Cl₂, washed with 2 N aqueous NaOH solution (2×0.75 mL), dried (MgSO₄) and concentrated. Chromatography (SiO₂, 6 to 8% CH₃OH/CH₂Cl₂ gradient elution) afforded 4-{(N-benzoylglycyl)amino)methyl-1-(compound No. 458) which was treated with TFA to give a TFA salt(105 mg, 97%): The purity was determined by RPLC/MS (85%); ESI/MS m/e 400 (M⁺+H, C₂₂H₂₆ClN₃O₂)

Examples 1060-1086

The compounds of this invention were synthesized pursuant to methods of Example 1059 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 25.

TABLE 25 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1060 459 C23 H28 Cl N3 O2 414 86* 78 Example 1061 460 C23 H28 Cl N3 O2 414 55 quant Example 1062 461 C23 H25 Cl F3 N3 O2 468 65 quant Example 1063 462 C23 H28 Cl N3 O2 414 61 quant Example 1064 463 C23 H28 Cl N3 O2 414 54 quant Example 1065 464 C25 H32 Cl N3 O5 490 56 quant Example 1066 465 C21 H25 Cl N4 O2 401 38 96 Example 1067 466 C22 H25 Cl N4 O4 445 15 34 Example 1068 557 C23 H28 Cl N3 O2 414 58* 66 Example 1069 558 C23 H28 Cl N3 O2 414 55 quant Example 1070 618 C25 H32 Cl N3 O2 442 58 quant Example 1071 686 C26 H34 Cl N3 O2 456 62 quant Example 1072 749 C34 H37 Cl N4 O2 569  7.2* 18 Example 1073 750 C24 H30 Cl N3 O3 444  4.7* 14 Example 1074 840 C24 H29 Cl N2 O2 413 52* 58 Example 1075 841 C23 H27 Cl N2 O2 399 52 quant Example 1076 842 C23 H26 Cl2 N2 O2 433 55 quant Example 1077 843 C25 H31 Cl N2 O2 427 58 quant Example 1078 844 C24 H29 Cl N2 O2 413 56 quant Example 1079 845 C24 H29 Cl N2 O4 S 477 62 quant Example 1080 846 C29 H31 Cl N2 O3 491 43 88 Example 1081 847 C24 H28 Cl F N2 O3 447 54 quant Example 1082 848 C25 H31 Cl N2 O2 427 47 quant Example 1083 849 C25 H31 Cl N2 O4 459 55 quant Example 1084 850 C22 H27 Cl N2 O3 S 435 46 quant Example 1085 873 C20 H28 Cl N3 O2 378 44.8 quant Example 1086 874 C23 H27 Cl2 N3 O3 464 51 quant *Yield of TFA salt.

Reference Example 19 Preparation of 1-(4-Chlorobenzyl)-4-{N-(3,3-diphenylpropyl)aminomethyl}piperidine

4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was alkylated with 3,3-diphenylpropyl methanesulfonate (1.0 equiv.) in the presence of NaI (2.6 equiv.) in CH₃CN at 70° C. for 16 h. General workup and column chromatography (SiO₂) afforded 1-(4-chlorobenzyl)-4-{N-(3,3-diphenylpropyl)aminomethyl}piperidine (118 mg, 54%): The purity was determined by RPLC (98%).

Reference Example 20 Preparation of 1-(4-Chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine

Reductive amination of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) with 2,2-diphenylacetaldehyde (0.66 equiv.) and polymer-supported borohydride in methanol at 25° C. for 16 h, followed by general workup and column chromatography (SiO₂) afforded 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (70 mg, 49%): The purity was determined by RPLC (98%).

Example 1087 Preparation of 4-{N-(N-Benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl}-1-(4-chlorobenzyl)piperidine (Compound No. 524)

A solution of 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (0.084 mmol) in CH₂Cl₂ was treated with hippuric acid (1.1 equiv.), HBTU (1.1 equiv.), HOBt (1.1 equiv.). The reaction mixture was stirred at 40° C. for 24 h. General workup and preparative TLC (SiO₂) afforded 4-{N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl}-1-(4-chlorobenzyl)piperidine (Compound No. 524) (8.5 mg, 17%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 580 (M⁺+H, C₃₆H₃₈ClN₃O₂).

Examples 1088-1090

The compounds of this invention were synthesized pursuant to methods of Example 1087 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 26.

TABLE 26 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1088 521 C38 H39 Cl F3 N3 O2 662 5.5 10 Example 1089 522 C37 H37 Cl F3 N3 O2 648 8.6 16 Example 1090 523 C37 H40 Cl N3 O2 594 4.8 10

Reference Example 21 Preparation of 1-(4-Chlorobenzyl)-4-{(valylamino)methyl}piperidine

A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol) in CH₂Cl₂ (21 mL) was treated with Et₃N (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH₂Cl₂ (20 mL), and washed with 2 N NaOH solution (2×20 mL), brine (1×20 mL) and dried (MgSO₄). Concentration and chromatography (SiO₂, 3% CH₃OH/CH₂Cl₂) afforded 1-(4-chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 60%) as a pale amber oil: ESI/MS m/e 438 (M⁺+H).

1-(4-Chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 2.51 mmol) was dissolved in 3 M HCl-CH₃OH solution (25 mL) and stirred at 25° C. for 1 h. The reaction mixture was concentrated and the resulting salt was dissolved in 3:1 ^(t)BuOH—H₂O (25 mL). Anion (OH⁻) exchange resin was added until the solution was slightly basic. Filtration and concentration afforded 1(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (819 mg, 97%) which required no further purification: RPLC (97%); ESI/MS 338.1 (M⁺+H, C₁₉H₂₈ClN₃O).

Other 4-{(acylamino)methyl}-1-(4-chlorobenzyl)piperidines were also synthesized pursuant to methods of Reference Example 20 using the corresponding reactant respectively.

1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine: 0.830 g, 67% (2 steps); ESI/MS 269 (M⁺+H).

1-(4-chlorobenzyl)-4-{(serylamino)methyl}piperidine: 0.286 g, 20% (2 steps); ESI/MS 326 (M⁺+H).

4-{(alanylamino)methyl}-1-(4-chlorobenzyl)piperidine: 1.20 g, 65% (2 steps); ESI/MS 310 (M⁺+H).

1-(4-chlorobenzyl)-4-{(prolylamino)methyl}piperidine: 1.48 g, 86% (2 steps); ESI/MS 336 (M⁺+H).

1-(4-chlorobenzyl)-4-{(glutaminylamino)methyl}piperidine: 0.830 g, 27% (2 steps); ESI/MS 367 (M⁺+H).

1-(4-chlorobenzyl)-4-{((2-methylalanyl)amino)methyl}piperidine: 2.24 g, 62% (2 steps); ESI/MS 324 (M⁺+H).

1-(4-chlorobenzyl)-4-{((O-methylseryl)amino)methyl}piperidine: 0.686 g, 38% (2 steps); ESI/MS 340 (M⁺+H).

1-(4-chlorobenzyl)-4-{((1-aminocyclopropylcarbonyl)amino)methyl}piperidine: 2.03 g, 82% (2 steps); ESI/MS 322 (M⁺+H).

1-(4-chlorobenzyl)-4-{(leucylamino)methyl}piperidine: 1.30 g, 58% (2 steps); ESI/MS 352 (M⁺+H).

1-(4-chlorobenzyl)-4-{((O-benzylseryl)amino)methyl}piperidine: 1.34 g, 56% (2 steps); ESI/MS 416 (M⁺+H).

Reference Example 22 Preparation of 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine

A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (5.72 g) in CH₂Cl₂ (150 mL) was treated with Et₃N (3.51 g), N-(9-fluorenylmethyloxycarbonyl)glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g). After the reaction mixture was stirred at room temperature for 5 h, the mixture was washed with water (100 mL×3) and brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from CH₃CN/CH₃OH (150 mL/1 mL) at 0° C. afforded 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (5.7 5 g, 44%) as pale yellow crystals.

Reference Example 23 Preparation of 4-[{N-(9-Fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine

To 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (3.17 g, 6.42 mmol) was added 4 N HCl in dioxane (50 mL). The solution was stirred at room temperature for 5 h. The reaction mixture was concentrated to give 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (3.85 g) as a white solid. The product was used without further purification.

Reference Example 24 Preparation of 4-[{N-(9-Fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-methylthiobenzyl)piperidine.

To A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.00 g, 2.33 mmol) in 1% AcOH/DMF (15 mL) were added 4-methylthiobenzaldehyde (1.24 g) and NaBH (OAc). (2.56 g). The reaction mixture was stirred at 60° C. for 1 h, cooled to room temperature, and concentrated. Saturated aqueous NaHCO₃ solution (50 mL) was added and the mixture was extracted with AcOEt (50 mL×2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, 5%-10% CH₃OH/CH₂Cl₂) afforded 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-methylthiobenzyl)piperidine (602 mg) as a colorless oil.

Reference Example 25 Preparation of 1-(4-Ethylbenzyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine

To A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.00 g, 2.33 mmol) in 2.5% AcOH/CH₃OH (80 mL) were added 4-ethylbenzaldehyde (1.09 g, 8.16 mmol) and NaBH₃CN (6.59 g, 10.5 mmol). The reaction mixture was stirred at 60° C. for 13 h. After the mixture was cooled to room temperature, 1 N aqueous NaOH solution (50 mL) and dichloromethane (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, CH₃OH/AcOEt 2:8) afforded 1-(4-ethylbenzyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (740 mg, 62%).

Reference Example 26 Preparation of 4-{(Glycylamino)methyl}-1-(4-methylthiobenzyl)piperidine

A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-methylthiobenzyl)piperidine (590 mg) and piperidine (1 mL) in DMF (4 mL) was stirred at room temperature for 2 h. Concentration and column chromatography (SiO₂, Et₃N:CH₃OH:CH₂Cl₂=1:1:9) afforded 4-{(glycylamino)methyl}-1-(4-methylthiobenzyl)piperidine (365 mg) as a white solid: ¹H NMR (CDCl₃, 270 MHz) δ 1.25(dd, J=12 Hz, 4.1 Hz, 2 H), 1.34(dd, J=12 Hz, 4.1 Hz, 2 H), 1.51 (br-s, 2 H), 1.66 (d, J=12 Hz, 2 H), 1.77 (d, J=7.3 Hz, 1 H), 1.94 (t, J=9.5 Hz, 2 H), 2.48 (s, 3 H), 2.80 (d, J=12 Hz, 2 H), 3.18 (t, J=6.2 Hz, 2 H), 3.35 (s, 2 H), 3.45 (s, 2 H), 7.18-7.29 (m, 4 H), 7.35 (br-s, 1 H).

1-(4-Ethylbenzyl)-4-{(glycylamino)methyl}piperidine was also synthesized pursuant to methods of Reference Example 25 using the corresponding reactant: 333 mg, 79%.

Reference Example 27 Preparation of 4-{(glycylamino)methyl}-1-(4-fluorobenzyl)piperidine

A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol), and Et₃N (1.47 mL, 10.5 mmol) in CH₃CN (200 mL) was stirred at room temperature for 13 h and concentrated. Column chromatography (SiO2, 10% CH₃OH/CH₂Cl₂) afforded 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine.

A solution of the 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine and piperidine (5 mL) in DMF (5 mL) was stirred at room temperature for 17 h. Concentration and column chromatography (SiO₂, Et₃N:CH₃OH:CH₂Cl₂=0.5:2:8) afforded 4-{(glycylamino)methyl)-1-(4-fluorobenzyl)piperidine (453 mg, 46%).

Reference Example 28 Preparation of 4-{(glycylamino)methyl}-1(4-(N-phenylcarbamoyl)benzyl}piperidine

To a mixture of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.27 g, 2.96 mmol), Et₃N (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and CH₃CN (200 mL) was added dropwise a solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) in CH₃ CN (100 mL). The mixture was stirred at room temperature for 19 h and at 60° C. for 5 h. Concentration and column chromatography (SiO₂, 5% CH₃OH/CH₂Cl₂-Et₃N:CH₃OH:CH₂Cl₂=2:2:96) afforded 4-{(glycylamino)methyl}-1-{4-(N-phenylcarbamoyl)benzyl}piperidine (340 mg, 30%).

Example 1091 Preparation of 1-(4-Chlorobenzyl)-4-[{N-(3-cyanobenzoyl)valyl}aminomethyl]piperidine (Compound No. 619)

A solution of 1-(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (20 mg, 0.059 mmol) in CH₂Cl₂ (0.60 mL) was treated with Et₃N (0.011 mL, 0.077 mmol), m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol). The reaction mixture was stirred at 25° C. for 16 h. The resulting solution was diluted with CH₂Cl₂ (0.75 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL) and dried by filtration through a PTFE membrane. Concentration afforded the 1-(4-chlorobenzyl)-4-[{N-(3-cyanobenzoyl)valyl}aminomethyl]piperidine (compound No. 619) (24.2 mg, 88%) which required no further purification: The purity was determined by RPLC/MS (85%); ESI/MS m/e 467 (M⁺+H, C₂₆H₃₁ClN₄O₂).

Examples 1092-1543

The compounds of this invention were synthesized pursuant to methods of Example 1091 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 27.

TABLE 27 Com- ESI/ pound MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1092  467 C22 H25 Br Cl N3 O2 478 11 46 Example 1093  468 C24 H31 Cl N4 O2 443 9 41 Example 1094  469 C23 H28 Cl N3 O3 430 7* 27 Example 1095  470 C23 H25 Cl N4 O2 425 21 quant Example 1096  471 C24 H28 Cl N3 O4 458 7 29 Example 1097  472 C29 H31 N3 O3 504 5* 21 Example 1098  473 C24 H28 Cl N3 O3 442 16 71 Example 1099  474 C23 H25 Cl F3 N3 O2 468 14 60 Example 1100  475 C25 H32 Cl N3 O2 442 5 22 Example 1101  476 C22 H25 Cl N4 O4 445 4 17 Example 1102  477 C25 H32 Cl N3 O3 458 10* 36 Example 1103  478 C21 H27 Cl N4 O2 403 9 47 Example 1104  479 C20 H24 Cl N3 O3 390 17 87 Example 1105  480 C20 H23 Br Cl N3 O3 470 23 quant Example 1106  481 C20 H24 Cl N3 O2 S 406 7 33 Example 1107  482 C21 H26 Cl N3 O2 S 420 9 45 Example 1108  483 C21 H26 Cl N3 O2 S 420 8 40 Example 1109  484 C24 H27 Cl N4 O2 439 9* 34 Example 1110  485 C24 H24 Cl F6 N3 O2 536 13 49 Example 1111  486 C23 H25 Cl N4 O2 425 16 74 Example 1112  487 C22 H25 Cl2 N3 O2 434 5 24 Example 1113  488 C22 H27 Cl N4 O2 415 7 32 Example 1114  489 C24 H24 Cl F6 N3 O2 536 21 78 Example 1115  490 C24 H30 Cl N3 O3 444 8 35 Example 1116  491 C23 H24 Cl F4 N3 O2 486 19 79 Example 1117  492 C23 H25 Cl F3 N3 O3 484 18 76 Example 1118  493 C23 H24 Cl2 F3 N3 O2 502 23 92 Example 1119  494 C23 H24 Cl F4 N3 O2 486 19 79 Example 1120  495 C23 H24 Cl F4 N3 O2 486 20 83 Example 1121  496 C23 H24 Cl F4 N3 O2 486 12 48 Example 1122  497 C25 H32 Cl N3 O3 458 4 16 Example 1123  498 C23 H26 Cl F3 N4 O2 483 13 52 Example 1124  499 C24 H31 Cl N4 O2 443 8 36 Example 1125  500 C23 H28 Cl N3 O3 430 10 48 Example 1126  501 C22 H24 Br Cl N4 O4 523 10 39 Example 1127  502 C22 H24 Cl F N4 O4 463 4 17 Example 1128  503 C22 H24 Cl2 N4 O4 479 12 52 Example 1129  504 C24 H30 Cl N3 O4 460 11 43 Example 1130  505 C22 H24 Br Cl N4 O4 523 2  8 Example 1131  506 C20 H23 Cl N4 O5 435 2 10 Example 1132  507 C21 H26 Cl N3 O3 404 9 44 Example 1133  508 C24 H26 Cl N3 O2 S 456 1  5 Example 1134  509 C20 H23 Br Cl N3 O2 S 484 12 48 Example 1135  510 C22 H28 Cl N3 O3 418 9 44 Example 1136  511 C24 H32 Cl N3 O3 446 9 40 Example 1137  512 C25 H29 Cl N4 O2 453 10 45 Example 1138  513 C24 H28 Cl N3 O3 442 9 41 Example 1139  514 C26 H34 Cl N3 O2 456 11 49 Example 1140  515 C23 H28 Cl N3 O3 430 5 24 Example 1141  525 C23 H28 Cl N3 O4 S 478 20 85 Example 1142  526 C20 H24 Cl N3 O3 390 6 31 Example 1143  527 C20 H24 Cl N3 O2 S 406 8 39 Example 1144  528 C25 H30 Cl F3 N4 O4 543 28.2 95 Example 1145  529 C20 H23 Cl N4 O4 S 451 9 39 Example 1146  530 C31 H33 Cl N4 O2 529 5 17 Example 1147  531 C21 H26 Cl N3 O3 S 436 8 37 Example 1148  532 C22 H28 Cl N3 O3 418 8 40 Example 1149  533 C21 H26 Cl N3 O3 404 6 32 Example 1150  534 C21 H25 Cl N4 O5 449 5 20 Example 1151  535 C22 H26 Cl N3 O3 S 448 8 37 Example 1152  536 C23 H31 Cl N4 O2 431 6 28 Example 1153  537 C25 H34 Cl N3 O3 460 8 34 Example 1154  538 C27 H30 Cl N3 O3 480 9 36 Example 1155  539 C22 H25 Cl F3 N3 O3 472 18 75 Example 1156  540 C25 H29 Cl N4 O2 453 8 36 Example 1157  541 C22 H26 Cl N5 O4 460 2.4 10 Example 1158  542 C24 H30 Cl N3 O2 428 4.6* 51 Example 1159  543 C24 H30 Cl N3 O2 428 20.6* 71 Example 1160  544 C22 H25 Cl F N3 O2 418 15.8* 56 Example 1161  545 C22 H24 Cl3 N3 O2 468 7.3* 23 Example 1162  546 C22 H24 Cl3 N3 O2 468 17.4* 55 Example 1163  547 C22 H24 Cl3 N3 O2 468 14.1* 44 Example 1164  548 C22 H24 Cl3 N3 O2 468 6.8* 22 Example 1165  549 C22 H24 Cl2 N4 O4 479 5.7* 18 Example 1166  550 C22 H24 Cl2 N4 O4 479 18.9* 58 Example 1167  551 C24 H30 Cl N3 O2 428 14.2* 49 Example 1168  552 C24 H27 Cl F3 N3 O2 482 30.6* 94 Example 1169  553 C25 H26 Cl F6 N3 O2 550 38.0* quant Example 1170  554 C24 H26 Cl F N4 O2 457 0.9*  3 Example 1171  555 C24 H26 Cl2 N4 O2 473 11.1* 35 Example 1172  556 C25 H29 Cl N4 O2 453 12.5* 41 Example 1173  559 C25 H26 Cl F6 N3 O2 550 15 72 Example 1174  560 C24 H27 Cl N4 O2 439 12 68 Example 1175  561 C23 H27 Br Cl N3 O2 494 14 73 Example 1176  562 C23 H27 Cl2 N3 O2 448 13 75 Example 1177  563 C25 H26 Cl F6 N3 O2 550 14 66 Example 1178  564 C25 H32 Cl N3 O3 458 5 28 Example 1179  565 C24 H26 Cl F4 N3 O2 500 12 61 Example 1180  566 C24 H27 Cl F3 N3 O3 498 12 62 Example 1181  567 C24 H26 Cl2 F3 N3 O2 516 12 61 Example 1182  568 C24 H26 Cl F4 N3 O2 500 15 77 Example 1183  569 C24 H26 Cl F4 N3 O2 500 11 59 Example 1184  570 C24 H26 Cl F4 N3 O2 500 16 84 Example 1185  571 C26 H34 Cl N3 O3 472 14 77 Example 1186  572 C24 H28 Cl F3 N4 O2 497 11 55 Example 1187  573 C21 H25 Br Cl N3 O2 S 500 12 64 Example 1188  574 C21 H25 Br Cl N3 O2 S 500 15 75 Example 1189  575 C25 H34 Cl N3 O3 460 16 87 Example 1190  576 C22 H28 Cl N3 O2 S2 466 13 71 Example 1191  577 C22 H28 Cl N3 O3 418 12 72 Example 1192  578 C25 H28 Cl N3 O2 S 470 15 81 Example 1193  579 C25 H29 Cl N4 O2 453 17 94 Example 1194  580 C22 H28 Cl N3 O2 S 434 15 91 Example 1195  581 C21 H26 Cl N3 O2 S 420 13 80 Example 1196  582 C22 H28 Cl N3 O2 S 434 10 59 Example 1197  583 C26 H31 Cl N4 O2 467 6 31 Example 1198  584 C30 H32 Cl N3 O3 518 18 92 Example 1199  585 C24 H27 Cl N4 O2 439 14 85 Example 1200  586 C23 H27 Cl2 N3 O2 448 17 97 Example 1201  587 C24 H27 Cl F3 N3 O2 482 17 91 Example 1202  588 C23 H29 Cl N4 O2 429 5 29 Example 1203  589 C27 H36 Cl N3 O2 470 4 24 Example 1204  590 C26 H34 Cl N3 O2 456 6 36 Example 1205  591 C25 H33 Cl N4 O2 457 7 38 Example 1206  592 C24 H30 Cl N3 O3 444 4 20 Example 1207  593 C24 H30 Cl N3 O3 444 2 14 Example 1208  594 C23 H28 Cl N3 O3 430 4 25 Example 1209  595 C25 H30 Cl N3 O4 472 7 38 Example 1210  596 C25 H30 Cl N3 O3 456 7 40 Example 1211  597 C25 H30 Cl N3 O3 456 15 85 Example 1212  598 C21 H26 Cl N3 O3 404 15 94 Example 1213  599 C22 H29 Cl N4 O2 417 5 30 Example 1214  600 C21 H25 Br Cl N3 O3 484 6 34 Example 1215  601 C24 H30 Cl N3 O3 444 5 28 Example 1216  602 C25 H33 Cl N4 O2 457 5 28 Example 1217  603 C23 H29 Cl N4 O2 429 4 22 Example 1218  604 C21 H27 Cl N4 O2 403 9 58 Example 1219  605 C21 H26 Cl N3 O3 404 17 87 Example 1220  606 C21 H26 Cl N3 O2 S 420 15 74 Example 1221  607 C22 H28 Cl N3 O3 S 450 31 quant Example 1222  608 C23 H30 Cl N3 O3 432 17 80 Example 1223  609 C22 H28 Cl N3 O3 418 18 89 Example 1224  610 C23 H28 Cl N3 O3 S 462 20 86 Example 1225  611 C26 H36 Cl N3 O3 474 21 90 Example 1226  612 C28 H32 Cl N3 O3 494 20 84 Example 1227  613 C23 H27 Cl F3 N3 O3 486 19 81 Example 1228  614 C24 H33 Cl N4 O2 445 23 quant Example 1229  615 C25 H29 Cl N4 O2 453 4 20 Example 1230  616 C32 H35 Cl N4 O2 543 11 40 Example 1231  617 C25 H27 Cl F3 N3 O2 482 6.7 37 Example 1232  620 C25 H31 Br Cl N3 O2 520 15 49 Example 1233  621 C25 H31 Cl2 N3 O2 476 18 64 Example 1234  622 C27 H37 Cl N4 O2 485 14 50 Example 1235  623 C26 H34 Cl N3 O3 472 19 69 Example 1236  624 C25 H31 Cl N4 O4 487 21 73 Example 1237  625 C25 H33 Cl N4 O2 457 19 69 Example 1238  626 C27 H30 Cl F6 N3 O2 578 8 25 Example 1239  627 C27 H36 Cl N3 O3 486 16 55 Example 1240  628 C27 H34 Cl N3 O4 500 24 80 Example 1241  629 C26 H30 Cl F4 N3 O2 528 18 56 Example 1242  630 C26 H31 Cl F3 N3 O3 526 21 68 Example 1243  631 C26 H30 Cl2 F3 N3 O2 544 15 48 Example 1244  632 C26 H30 Cl F4 N3 O2 528 13 41 Example 1245  633 C26 H30 Cl F4 N3 O2 528 20 63 Example 1246  634 C26 H30 Cl F4 N3 O2 528 19 62 Example 1247  635 C28 H38 Cl N3 O3 500 11 36 Example 1248  636 C26 H34 Cl N3 O2 456 21 89 Example 1249  637 C26 H31 Cl F3 N3 O2 510 20 95 Example 1250  638 C26 H31 Cl N4 O2 467 15 54 Example 1251  639 C27 H37 Cl N4 O2 485 19 66 Example 1252  640 C26 H34 Cl N3 O3 472 16 56 Example 1253  641 C27 H34 Cl N3 O4 500 18 59 Example 1254  642 C32 H36 Cl N3 O3 546 24 73 Example 1255  643 C26 H31 Cl F3 N3 O2 510 16 54 Example 1256  644 C29 H40 Cl N3 O2 498 18 61 Example 1257  645 C25 H33 Cl N4 O2 457 22 78 Example 1258  646 C26 H34 Cl N3 O3 472 13 47 Example 1259  647 C27 H34 Cl N3 O3 500 13 46 Example 1260  648 C28 H38 Cl N3 O2 484 17 60 Example 1261  649 C28 H38 Cl N3 O3 500 12.5 42 Example 1262  650 C32 H36 Cl N3 O3 546 1*  2 Example 1263  651 C28 H35 Cl N4 O2 495 4* 12 Example 1264  652 C25 H31 Cl N4 O4 487 5* 14 Example 1265  653 C30 H42 Cl N3 O3 528 1*  3 Example 1266  654 C27 H34 Cl N3 O3 484 7* 21 Example 1267  655 C26 H32 Cl F3 N4 O2 525 6* 16 Example 1268  656 C23 H30 Cl N3 O3 432 6* 18 Example 1269  657 C23 H30 Cl N3 O2 S 448 4* 13 Example 1270  658 C27 H33 Cl N4 O2  48 1*  4 Example 1271  659 C23 H29 Cl N4 O4 S 493 4* 10 Example 1272  660 C34 H39 Cl N4 O2 571 3*  7 Example 1273  661 C24 H32 Cl N3 O3 S 478 3*  7 Example 1274  662 C25 H34 Cl N3 O3 460 2*  6 Example 1275  663 C24 H32 Cl N3 O3 446 2*  5 Example 1276  664 C24 H31 Cl N4 O5 491 2*  5 Example 1277  665 C25 H32 Cl N3 O3 S 490 1*  3 Example 1278  666 C26 H37 Cl N4 O2 473 3*  7 Example 1279  667 C30 H36 Cl N3 O3 522 3*  7 Example 1280  668 C25 H31 Cl F3 N3 O3 514 2*  6 Example 1281  669 C24 H33 Cl N4 O2 445 15* 45 Example 1282  670 C23 H29 Br Cl N3 O3 510 3*  7 Example 1283  671 C23 H29 Cl N4 O5 477 2*  5 Example 1284  672 C23 H31 Cl N4 O2 431 2*  7 Example 1285  673 C23 H30 Cl N3 O2 S 448 2*  6 Example 1286  674 C24 H32 Cl N3 O2 S 462 3*  9 Example 1287  675 C24 H32 Cl N3 O2 S 462 1*  4 Example 1288  676 C27 H33 Cl N4 O2 482 2*  6 Example 1289  677 C28 H35 Cl N4 O2 495 2*  6 Example 1290  678 C24 H32 Cl N3 O3 446 3*  9 Example 1291  679 C27 H32 Cl N3 O2 S 498 1*  3 Example 1292  680 C23 H29 Br Cl N3 O2 S 526 2*  6 Example 1293  681 C25 H34 Cl N3 O3 460 2*  5 Example 1294  682 C27 H38 Cl N3 O3 488 2*  4 Example 1295  683 C24 H32 Cl N3 O2 S2 494 1*  4 Example 1296  684 C26 H36 Cl N3 O4 S2 554 2*  5 Example 1297  685 C24 H32 Cl N3 O4 S2 526 3*  7 Example 1298  687 C25 H30 Cl N3 O2 440 24 quant Example 1299  688 C27 H28 Cl F6 N3 O2 576 28 98 Example 1300  689 C26 H29 Cl N4 O2 465 23 99 Example 1301  690 C25 H29 Br Cl N3 O2 518 26 99 Example 1302  691 C27 H35 Cl N4 O2 483 24 97 Example 1303  692 C26 H32 Cl N3 O3 470 24 quant Example 1304  693 C27 H28 Cl F6 N3 O2 576 16 55 Example 1305  694 C27 H34 Cl N3 O3 484 25 quant Example 1306  695 C27 H32 Cl N3 O4 498 12 47 Example 1307  696 C26 H29 Cl F3 N3 O3 524 25 95 Example 1308  697 C26 H29 Cl N4 O2 465 15 64 Example 1309  698 C27 H35 Cl N4 O2 483 24 quant Example 1310  699 C26 H32 Cl N3 O3 470 26 quant Example 1311  700 C27 H32 Cl N3 O4 498 15 62 Example 1312  701 C27 H32 Cl N3 O3 482 11 44 Example 1313  702 C26 H29 Cl F3 N3 O2 508 23 94 Example 1314  703 C28 H36 Cl N3 O2 482 26 quant Example 1315  704 C25 H29 Cl N4 O4 485 11 43 Example 1316  705 C24 H30 Cl N3 O2 S 460 25 quant Example 1317  706 C24 H30 Cl N3 O2 S 460 25 quant Example 1318  707 C26 H29 Cl F3 N3 O2 508 15 55 Example 1319  708 C23 H27 Br Cl N3 O2 S 526 25 92 Example 1320  709 C24 H30 Cl N3 O2 S2 492 26 quant Example 1321  710 C23 H27 Br Cl N3 O2 S 526 25 94 Example 1322  711 C25 H32 Cl N3 O3 458 26 quant Example 1323  712 C27 H30 Cl N3 O2 S 496 26 quant Example 1324  713 C24 H30 Cl N3 O3 444 26 quant Example 1325  714 C28 H33 Cl N4 O2 493 12 50 Example 1326  715 C23 H28 Cl N3 O2 S 446 24 quant Example 1327  716 C27 H31 Cl N4 O2 479 32 quant Example 1328  717 C23 H27 Cl N4 O5 475 23 95 Example 1329  718 C23 H29 Cl N4 O2 429 24 quant Example 1330  719 C23 H28 Cl N3 O3 430 24 quant Example 1331  720 C23 H27 Br Cl N3 O3 510 24 95 Example 1332  721 C24 H31 Cl N4 O2 443 22 98 Example 1333  722 C26 H32 Cl N3 O3 470 9 37 Example 1334  723 C25 H31 Cl N4 O2 455 10 44 Example 1335  724 C29 H38 Cl N3 O2 496 28 quant Example 1336  725 C32 H34 Cl N3 O3 544 26 95 Example 1337  726 C27 H33 Cl N4 O3 497 3 11 Example 1338  727 C25 H29 Cl2 N3 O2 474 25 quant Example 1339  728 C25 H31 Cl N4 O2 455 21 92 Example 1340  729 C25 H29 Cl N4 O4 485 26 quant Example 1341  730 C25 H29 Cl2 N3 O2 474 21 90 Example 1342  731 C27 H32 Cl N3 O3 482 10 41 Example 1343  732 C26 H28 Cl F4 N3 O2 526 27 quant Example 1344  733 C28 H36 Cl N3 O3 498 22 89 Example 1345  734 C26 H28 Cl F4 N3 O2 526 25 94 Example 1346  735 C26 H28 Cl F4 N3 O2 526 23 87 Example 1347  736 C26 H30 Cl F3 N4 O2 523 24 78 Example 1348  737 C26 H28 Cl F4 N3 O2 526 21 66 Example 1349  738 C25 H32 Cl N3 O3 458 23 84 Example 1350  739 C27 H31 Cl N4 O2 479 19 66 Example 1351  740 C24 H31 Cl N4 O5 489 23 77 Example 1352  741 C23 H27 Cl N4 O4 S 491 26 88 Example 1353  742 C24 H30 Cl N3 O3 S 476 23 82 Example 1354  743 C23 H28 Cl N3 O3 430 21 81 Example 1355  744 C26 H32 Cl N3 O2 454 25 91 Example 1356  745 C27 H36 Cl N3 O3 486 23 80 Example 1357  746 C26 H35 Cl N4 O2 471 27 96 Example 1358  747 C25 H29 Cl F3 N3 O3 512 23 74 Example 1359  748 C23 H28 Cl N3 O2 S 446 22 82 Example 1360  751 C24 H30 Cl N3 O3 444 3 11 Example 1361  752 C25 H26 Cl F6 N3 O3 566 7 20 Example 1362  753 C24 H27 Cl N4 O3 455 6 22 Example 1363  754 C23 H27 Cl2 N3 O3 464 8 29 Example 1364  755 C24 H30 Cl N3 O4 460 6 22 Example 1365  756 C23 H27 Cl N4 O5 475 5 18 Example 1366  757 C25 H32 Cl N3 O4 474 5 18 Example 1367  758 C25 H30 Cl N3 O5 488 5 18 Example 1368  759 C24 H27 Cl F3 N3 O4 514 6 20 Example 1369  760 C24 H26 Cl F4 N3 O3 516 6 18 Example 1370  761 C24 H26 Cl F4 N3 O3 516 3 10 Example 1371  762 C24 H27 Cl F3 N3 O3 498 2 95 Example 1372  763 C23 H28 Cl N3 O3 430 4 95 Example 1373  764 C24 H30 Cl N3 O2 428 9 42 Example 1374  765 C25 H32 Cl N3 O2 442 10 47 Example 1375  766 C25 H29 Cl F3 N3 O2 496 10 42 Example 1376  767 C25 H32 Cl N3 O4 S 506 8 32 Example 1377  768 C24 H29 Br Cl N3 O2 506 9 35 Example 1378  769 C25 H29 Cl F3 N3 O3 512 6 22 Example 1379  770 C25 H28 Cl F4 N3 O2 514 3 10 Example 1380  771 C25 H28 Cl F4 N3 O2 514 10 37 Example 1381  772 C25 H29 Cl F3 N3 O2 496 8 33 Example 1382  773 C26 H36 Cl N3 O3 474 10 41 Example 1383  774 C23 H30 Cl N3 O2 S2 480 12 50 Example 1384  775 C27 H38 Cl N3 O3 488 14 57 Example 1385  776 C29 H34 Cl N3 O3 508 12 49 Example 1386  777 C24 H29 Cl F3 N3 O3 500 22 87 Example 1387  778 C24 H28 Cl2 N4 O4 507 6 22 Example 1388  779 C24 H29 Cl2 N3 O2 462 10 46 Example 1389  780 C24 H29 Cl N4 O4 473 15 65 Example 1390  781 C26 H31 Cl N4 O2 467 7* 20 Example 1391  782 C25 H32 Cl N3 O3 458 8* 23 Example 1392  783 C26 H34 Cl N3 O3 472 7* 19 Example 1393  784 C26 H31 Cl F3 N3 O2 510 7* 17 Example 1394  785 C26 H34 Cl N3 O4 488 6* 17 Example 1395  786 C24 H28 Cl N3 O2 426 22  9 Example 1396  787 C25 H30 Cl N3 O2 440 21 94 Example 1397  788 C25 H27 Cl F3 N3 O2 494 4* 14 Example 1398  789 C25 H30 Cl N3 O4 S 504 9 35 Example 1399  790 C24 H27 Cl2 N3 O2 460 5* 16 Example 1400  791 C24 H27 Cl N4 O4 471 3* 10 Example 1401  792 C25 H27 Cl F3 N3 O3 510 5* 16 Example 1402  793 C25 H26 Cl F4 N3 O2 511 5* 16 Example 1403  794 C25 H26 Cl F4 N3 O2 512 5* 16 Example 1404  795 C25 H27 Cl F3 N3 O2 494 6* 21 Example 1405  796 C23 H28 Cl N3 O2 S2 478 4* 14 Example 1406  797 C27 H36 Cl N3 O3 486 7* 29 Example 1407  798 C29 H32 Cl N3 O3 506 3 13 Example 1408  799 C24 H27 Cl F3 N3 O3 498 3* 11 Example 1409  800 C24 H26 Cl2 N4 O4 505 5* 15 Example 1410  801 C26 H29 Cl N4 O2 465 12 41 Example 1411  802 C25 H30 Cl N3 O3 456 5* 15 Example 1412  803 C26 H32 Cl N3 O3 470 6* 16 Example 1413  804 C26 H29 Cl F3 N3 O2 508 8* 20 Example 1414  805 C26 H32 Cl N3 O4 486 6* 15 Example 1415  806 C24 H27 Br Cl N3 O2 506 5* 14 Example 1416  807 C27 H32 Cl N5 O3 510 29.7 quant Example 1417  808 C26 H33 Cl N4 O3 485 29.9 quant Example 1418  809 C25 H30 Cl2 N4 O3 505 30.2 quant Example 1419  810 C30 H35 Cl N4 O4 551 31.0 quant Example 1420  811 C25 H29 Cl2 N5 O5 550 30.4 quant Example 1421  812 C24 H31 Cl N4 O3 S2 523 25.0 88 Example 1422  813 C26 H30 Cl F3 N4 O3 539 20.5 70 Example 1423  814 C26 H30 Cl F3 N4 O4 555 22.7 75 Example 1424  815 C26 H29 Cl F4 N4 O3 557 25.8 85 Example 1425  816 C26 H30 Cl F3 N4 O3 539 25.3 86 Example 1426  817 C26 H29 Cl F4 N4 O3 557 26.8 88 Example 1427  818 C25 H30 Br Cl N4 O3 551 27.1 90 Example 1428  819 C27 H29 Cl F6 N4 O3 607 13.9 42 Example 1429  820 C25 H30 Cl N5 O5 516 14.1 51 Example 1430  821 C24 H28 Cl2 N4 O5 523 40 86 Example 1431  822 C23 H30 Cl N3 O3 S2 496 41 93 Example 1432  823 C26 H31 Cl N4 O3 483 43 quant Example 1433  824 C27 H38 Cl N3 O4 503 37 83 Example 1434  825 C29 H34 Cl N3 O4 524 28 61 Example 1435  826 C24 H29 Cl F3 N3 O4 516 40 87 Example 1436  827 C26 H31 Cl N4 O3 483 31 72 Example 1437  828 C25 H29 Cl F3 N3 O4 528 40 86 Example 1438  829 C25 H28 Cl F4 N3 O3 530 45 97 Example 1439  830 C25 H28 Cl F4 N3 O3 530 35 74 Example 1440  831 C24 H29 Br Cl N3 O3 523 45 98 Example 1441  832 C24 H29 Cl2 N3 O3 478 38 91 Example 1442  833 C24 H29 Cl N4 O5 488 38 87 Example 1443  834 C25 H29 Cl F3 N3 O3 512 42 93 Example 1444  835 C24 H30 Cl N3 O3 444 43 quant Example 1445  836 C25 H32 Cl N3 O3 458 37 91 Example 1446  837 C25 H29 Cl F3 N3 O3 512 41 91 Example 1447  838 C26 H34 Cl N3 O4 488 34 78 Example 1448  839 C27 H36 Cl N3 O6 534 37 71 Example 1449  942 C27 H30 Cl F6 N3 O2 578 17 48 Example 1450  997 C26 H34 Cl N3 O2 456 7.6* 23 Example 1451  998 C27 H33 Cl F3 N3 O2 524 6 15 Example 1452  999 C27 H36 Cl N3 O2 470 8 24 Example 1453 1000 C27 H36 Cl N3 O3 486 9 24 Example 1454 1001 C28 H38 Cl N3 O3 500 4 10 Example 1455 1002 C27 H33 Cl F3 N3 O3 540 9 23 Example 1456 1003 C28 H38 Cl N3 O2 484 7 21 Example 1457 1004 C28 H38 Cl N3 O4 516 11 30 Example 1458 1005 C29 H40 Cl N3 O5 547 9 23 Example 1459 1006 C30 H42 Cl N3 O4 544 8 21 Example 1460 1007 C32 H46 Cl N3 O5 589 7 17 Example 1461 1008 C25 H31 Cl N4 O3 471 25 79 Example 1462 1009 C26 H33 Cl N4 O4 501 35 97 Example 1463 1010 C27 H35 Cl N4 O4 515 35  9 Example 1464 1011 C27 H35 Cl N4 O3 499 32 54 Example 1465 1012 C27 H35 Cl N4 O5 531 27 77 Example 1466 1013 C28 H37 Cl N4 O6 561 14 37 Example 1467 1014 C29 H39 Cl N4 O5 559 24 66 Example 1468 1015 C31 H43 Cl N4 O6 603 25 65 Example 1469 1018 C26 H34 Cl N3 O4 488 13.0* 39 Example 1470 1019 C28 H38 Cl N3 O5 532 13.4* 37 Example 1471 1020 C25 H32 Cl N3 O4 474 12.7* 40 Example 1472 1021 C26 H28 Cl F6 N3 O4 596 13.8* 34 Example 1473 1022 C25 H32 Cl N3 O4 474 14.2* 37 Example 1474 1023 C25 H32 Cl N3 O2 442 11.5* 32 Example 1475 1024 C26 H34 Cl N3 O5 504 12.0* 30 Example 1476 1025 C27 H36 Cl N3 O4 502 14.7* 37 Example 1477 1026 C29 H40 Cl N3 O5 546 13.5* 32 Example 1478 1027 C26 H34 Cl N3 O4 488 11.9* 31 Example 1479 1028 C27 H30 Cl F6 N3 O4 610 14.6* 31 Example 1480 1029 C25 H32 Cl N3 O3 458 14.0* 38 Example 1481 1030 C24 H27 Cl F3 N3 O3 498 14.0* 35 Example 1482 1031 C24 H30 Cl N3 O3 444 10.4* 29 Example 1483 1032 C25 H32 Cl N3 O4 474 14.9* 39 Example 1484 1033 C25 H32 Cl N3 O2 442 13.3* 37 Example 1485 1034 C26 H34 Cl N3 O5 504 13.7* 34 Example 1486 1035 C27 H36 Cl N3 O4 502 16.7* 42 Example 1487 1036 C29 H40 Cl N3 O5 547 15.5* 36 Example 1488 1037 C26 H34 Cl N3 O4 488 14.1* 36 Example 1489 1038 C27 H30 Cl F6 N3 O4 610 17.5* 37 Example 1490 1039 C25 H32 Cl N3 O3 458 15.1* 41 Example 1491 1040 C24 H27 Cl F3 N3 O3 498 15.4* 39 Example 1492 1041 C24 H30 Cl N3 O3 444 12.7* 35 Example 1493 1042 C22 H26 Br Cl N4 O2 495 10.4* 25 Example 1494 1043 C22 H26 Cl2 N4 O2 449 11.1* 29 Example 1495 1044 C23 H29 Cl N4 O2 429 5.2* 14 Example 1496 1045 C23 H29 Cl N4 O3 445 12.4* 33 Example 1497 1046 C22 H25 Cl3 N4 O2 483 10.0* 25 Example 1498 1047 C24 H31 Cl N4 O2 443 12.1* 32 Example 1499 1048 C25 H33 Cl N4 O5 505 16.1* 39 Example 1500 1049 C23 H28 Br Cl N4 O2 507 12.0* 29 Example 1501 1050 C28 H38 Cl N3 O4 516 39.2* quant Example 1502 1051 C28 H38 Cl N3 O2 484 34.0* quant Example 1503 1052 C29 H40 Cl N3 O5 546 14.5* 39 Example 1504 1053 C30 H42 Cl N3 O4 544 11.8* 32 Example 1505 1054 C32 H46 Cl N3 O5 588 12.2* 31 Example 1506 1055 C29 H40 Cl N3 O4 530 44.5* quant Example 1507 1056 C30 H36 Cl F6 N3 O4 652 46.0* quant Example 1508 1057 C28 H38 Cl N3 O3 500 11.2* 32 Example 1509 1058 C27 H36 Cl N3 O3 486 35.5* quant Example 1510 1059 C27 H33 Cl F3 N3 O3 540 41.4* quant Example 1511 1060 C29 H40 Cl N3 O4 530 13.6* 37 Example 1512 1061 C30 H36 Cl F6 N3 O4 652 44.2* quant Example 1513 1062 C28 H38 Cl N3 O3 500 39.9* quant Example 1514 1063 C27 H36 Cl N3 O3 486 12.0* 35 Example 1515 1064 C27 H33 Cl F3 N3 O3 540 37.8* quant Example 1516 1065 C28 H38 Cl N3 O4 516 12.3* 34 Example 1517 1066 C28 H38 Cl N3 O2 484 30.7* 90 Example 1518 1067 C29 H40 Cl N3 O5 546 13.8* 37 Example 1519 1068 C30 H42 Cl N3 O4 544 13.1* 35 Example 1520 1069 C32 H46 Cl N3 O5 589 14.1* 35 Example 1521 1070 C29 H34 Cl N3 O3 S2 572 38.3 93 Example 1522 1071 C32 H35 Cl N4 O3 559 39.6 98 Example 1523 1072 C33 H42 Cl N3 O4 580 40.9 98 Example 1524 1073 C35 H38 Cl N3 O4 600 40.5 94 Example 1525 1074 C30 H33 Cl F3 N3 O4 592 38.7 91 Example 1526 1075 C31 H33 Cl F3 N3 O4 604 38 87 Example 1527 1076 C30 H33 Cl N4 O5 565 38.5 94 Example 1528 1077 C31 H33 Cl F3 N3 O3 588 35.8 84 Example 1529 1078 C30 H34 Cl N3 O3 520 34.7 93 Example 1530 1079 C31 H36 Cl N3 O3 534 38.4 quant Example 1531 1080 C32 H38 Cl N3 O4 564 39.3 97 Example 1532 1081 C33 H40 Cl N3 O6 610 45.5 quant Example 1533 1082 C28 H36 Cl N3 O3 498 4.1* 10 Example 1534 1083 C28 H36 Cl N3 O3 498 6.4* 16 Example 1535 1125 C30 H32 Cl2 N4 O5 599 3.4*  8 Example 1536 1126 C30 H32 Br Cl N4 O5 644 3.4*  7 Example 1537 1127 C32 H35 Cl N4 O3 559 1.6*  4 Example 1538 1128 C31 H32 Cl F4 N3 O3 606 4.3* 10 Example 1539 1129 C31 H32 Cl F4 N3 O3 606 5.9* 14 Example 1540 1130 C30 H33 Br Cl N3 O3 599 5.7* 13 Example 1541 1131 C30 H33 Cl2 N3 O3 554 6.4* 16 Example 1542 1132 C31 H33 Cl F3 N3 O3 588 6.3* 15 Example 1543 1167 C27 H34 Cl N3 O3 484 1.8*  4 *Yield of TFA salt.

Example 1544 Preparation of 1-(4-Chlorobenzyl)-4-[{N-(3,5-bis(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1213).

A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a mixture of 1-(4-chlorobenzyl)-4{(glycylamino)methyl}piperidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 mL). After the reaction mixture was stirred at room temperature for 2 h, methanol (1.0 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH₃OH (16 mL). Product was eluted off using 2 N NH₃ in CH₃ OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3,5-bis(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1213) (24.0 mg, 90%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 536.2 (M⁺+H, C₂₄H₂₄ClF₆N₃O₂).

Examples 1545-1547.

The compounds of this invention were synthesized pursuant to methods of Example 1544 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 28.

TABLE 28 Com- ESI/ pound MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1545 1214 C23 H24 Cl F4 N3 O3 486.2 22.2 91 Example 1546 1215 C22 H24 Cl3 N3 O2 467.9 20.9 89 Example 1547 1216 C22 H24 Cl F2 N3 O2 436.0 19.3 89

Example 1548 Preparation of 4-[{N-(3-Bromo-4-methylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl piperidine (Compound No. 1113).

A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (0.050 mmol) in CHCl₃ (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH₃OH/CHCl₃ 1:1 (12 mL) and CH₃OH (12 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 4-[{N-(3-bromo-4-methylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1113) (16.1 mg, 65%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 494.0 (C₂₃H₂₇BrClN₃O₂).

Examples 1549-1619.

The compounds of this invention were synthesized pursuant to methods of Example 1548 using the corresponding reactant respectively. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 29.

Compound No. 1422 was obtained as by product of Compound No. 1418: 5.6 mg, 25% yield; ESI/MS m/e 447.2 (C₂₂H₂₇ClN₄O₃S).

TABLE 29 Com- ESI/ pound MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1549 1114 C₂₂H₂₄BrClFN₃O₂ 498.0 20.2 81 Example 1550 1115 C₂₂H₂₄Cl₂FN₃O₂ 452.2 18.6 82 Example 1551 1116 C₂₃H₂₇ClIN₃O₂ 539.1 21.9 81 Example 1552 1117 C₂₃H₂₇ClN₄O₄ 459.2 18.7 81 Example 1553 1187 C₂₃H₂₇BrClN₃O₂ 494.0 22.1 90 Example 1554 1188 C₂₄H₂₇ClN₄O₃ 455.2 17.2 76 Example 1555 1189 C₂₅H₂₉ClN₄O₃ 469.2 21.1 90 Example 1556 1190 C₂₂H₂₆ClFN₄O₂ 433.2 20.4 94 Example 1557 1241 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 22.5 90 Example 1558 1242 C₂₃H₂₇ClFN₃O₂ 432.2 21.2 98 Example 1559 1243 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.6 96 Example 1560 1244 C₂₂H₂₆ClIN₄O₂ 541.0 26.4 98 Example 1561 1245 C₂₂H₂₅ClF₂N₄O₂ 451.0 21.3 94 Example 1562 1246 C₂₁H₂₇ClN₄O₂ 403.2 19.4 96 Example 1563 1247 C₂₈H₃₀ClN₃O₂S 524.0 24.7 94 Example 1564 1248 C₂₂H₂₅ClN₄O₅ 461.0 20.7 90 Example 1565 1282 C₂₅H₂₆ClF₃N₄O₃ 523.2 25.0 96 Example 1566 1283 C₂₃H₂₇Cl₂N₃O₃ 464.2 12.2 53 Example 1567 1284 C₂₂H₂₅BrClN₃O₃ 496.0 24.1 97 Example 1568 1285 C₂₂H₂₅Cl₂N₃O₃ 450.2 21.8 97 Example 1569 1342 C₂₂H₂₄BrCl₂N₃O₂ 514.0 27.2 quant Example 1570 1343 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.4 95 Example 1571 1344 C₂₂H₂₄Cl₂IN₃O₂ 560.0 27.0 96 Example 1572 1345 C₂₃H₂₈ClN₃O₂ 430.2 23.8 quant Example 1573 1346 C₂₂H₂₅ClIN₃O₃ 542.0 29.4 quant Example 1574 1350 C₂₁H₂₆ClN₃O₂S 420.0 13.0 62 Example 1575 1354 C₂₄H₂₈BrClN₄O₃ 537.2 5.2 19 Example 1576 1358 C₂₃H₂₆ClN₅O₂ 440.2 21.8 99 Example 1577 1383 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 20.0 80 Example 1578 1384 C₂₀H₂₃BrClN₃O₂S 486.0 21.0 87 Example 1579 1385 C₂₈H₃₀ClN₃O₄S 540.2 23.8 88 Example 1580 1386 C₂₈H₃₀ClN₃O₂ 476.0 20.0 84 Example 1581 1414 C₂₄H₂₈Cl₂N₄0₃ 491.0 0.8  3 Example 1582 1418 C₂₃H₂₆ClN₅O₂S 472.0 10.4 44 Example 1583 1436 C29 H30 Cl N3 O3 504.2 26.8 quant Example 1584 1600 C23 H26 Cl F3 N4 O2 483.2 16.5 68 Example 1585 1601 C23 H26 Cl F3 N4 O3 499.0 20.0 80 Example 1586 1602 C21 H24 Br Cl N4 O2 481.0 18.1 75 Example 1587 1603 C21 H24 Cl2 N4 O2 435.0 5.5 25 Example 1588 1604 C27 H30 Cl N3 O3 492.0 18.6 76 Example 1589 1605 C21 H27 Cl N4 O2 415.2 18.1 87 Example 1590 1609 C23 H25 N3 O2 S 500.0 18.3 73 Example 1591 1659 C22 H26 Cl2 N4 O2 449.0 366.0 83 Example 1592 1664 C24 H29 F3 N4 O2 S 495.2 13.7 55 Example 1593 1665 C24 H29 F3 N4 O3 S 511.2 14.9 58 Example 1594 1666 C23 H28 F2 N4 O2 S 463.2 12.9 56 Example 1595 1667 C22 H27 Br2 N3 O3 542   26.1 96 Example 1596 1668 C24 H30 F2 N4 O2 445   22.9 quant Example 1597 1669 C24 H31 F N4 O2 427   24.0 quant Example 1598 1670 C24 H31 I N4 O2 535   28.1 quant Example 1599 1671 C25 H31 F3 N4 O3 493   26.8 quant Example 1600 1672 C25 H31 F3 N4 O2 478   24.7 quant Example 1601 1673 C24 H29 Br Cl N3 O2 508   24.9 98 Example 1602 1674 C20 H22 Br2 F N3 O3 532   25.6 96 Example 1603 1675 C22 H25 F3 N4 O2 435   21.5 99 Example 1604 1676 C22 H26 F2 N4 O2 417   21.4 quant Example 1605 1677 C22 H26 Br F N4 O2 479   23.4 98 Example 1606 1678 C22 H26 F I N4 O2 525   27.4 quant Example 1607 1679 C22 H26 Cl F N4 O2 433   22.4 quant Example 1608 1680 C23 H26 F4 N4 O3 483   25.5 quant Example 1609 1681 C23 H26 F4 N4 O2 467   23.2 99 Example 1610 1682 C23 H26 Br Cl F N3 O 498   24.2 98 Example 1611 1683 C27 H28 Br2 N4 O4 633   31.8 quant Example 1612 1684 C29 H31 F2 N5 O3 536   28.3 quant Example 1613 1685 C29 H32 F N5 O3 518   31.1 quant Example 1614 1686 C29 H32 Br N5 O3 578   29.6 quant Example 1615 1687 C29 H32 I N5 O3 626   32.4 quant Example 1616 1688 C29 H32 Cl N5 O3 534   28.2 quant Example 1617 1689 C30 H32 F3 N5 O4 584   31.7 quant Example 1618 1690 C30 H32 F3 N5 O3 568   30.6 quant Example 1619 1691 C29 H30 Br Cl N4 O3 599   31.4 quant

For example, Compound 1245 and 1600 showed the following NMR spectra.

Compound No. 1245: ¹H NMR (270 MHz, CDCl₃) δ 1.20-1.97 (m, 7 H), 2.80-2.86 (m, 2 H), 3.19 (t, J=6.5 Hz, 2 H), 3.43 (s, 2 H), 4.02 (d, J=5.3 Hz, 2 H), 5.52 (br s, 2 H), 6.44 (d, J=11.9, 6.6 Hz, 1 H), 7.02 (br s, 1 H), 7.21-7.32 (m, 5 H).

Compound No. 1600: ¹H NMR (270 MHz, CDCl₃) δ 1.25-1.97 (m, 9 H), 2.82-2.87 (m, 2 H), 3.21 (t, J=6.5 Hz, 2 H), 3.44 (s, 2 H), 4.06 (d, J=5.1 Hz, 2 H), 5.98 (br s, 1 H), 6.71 (d, J=8.3 Hz, 1 H), 6.87 (br s, 1 H), 7.26 (s, 4 H), 7.43 (dd, J=5.9 Hz, 1 H), 7.64 (s, 1 H).

Example 1620 Preparation of 1-(4-Chlorobenzyl)-4-[{N-(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (Compound No. 869).

A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHCl₃ (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined by RPLC/MS (86%); ESI/MS m/e 478 (M⁺+H, C₂₄H₃₂ClN₃O₃ S).

Examples 1621-627.

The compounds of this invention were synthesized pursuant to methods of Example 1620 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 30.

TABLE 30 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 865 C22 H28 Cl N3 O3 S 450 16.2 72 1621 Example 866 C22 H25 Cl F3 N3 O3 S 504 8.8 35 1622 Example 867 C23 H24 Cl F6 N3 O3 S 572 8.0 28 1623 Example 868 C23 H30 Cl N3 O3 S 464 9.6 41 1624 Example 870 C22 H28 Cl N3 O3 S 450 8.8 39 1625 Example 871 C25 H34 Cl N3 O3 S 492 11.1 45 1626 Example 872 C21 H26 Cl N3 O3 S 436 9.6 44 1627

Example 1628 Preparation of 1-(4-Chlorobenzyl)-4-[{2-(3-(4-trifluoromethylphenyl)ureido)acetylamino}methyl]piperidine (Compound No. 852).

A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHCl₃ (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 3-(trifluoromethyl)phenyl isocyanate (1.3 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual isocyanate and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{2-(3-(4-trifluoromethylphenyl)ureido)acetylamino}methyl]piperidine (19 mg, 78%) (compound No. 852): The purity was determined by RPLC/MS (92%); ESI/MS m/e 483 (M⁺+H, C₂₃H₂₆ClF₃N₄O₂)

Examples 1629-1641.

The compounds of this invention were synthesized pursuant to methods of Example 1628 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 31.

TABLE 31 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 851 C23 H26 Cl F3 N4 O2 483 13.2 55 1629 Example 853 C22 H27 Cl N4 O2 416  8.5* 32 1630 Example 854 C23 H29 Cl N4 O2 429  11.4* 42 1631 Example 855 C23 H29 Cl N4 O2 429  10.1* 37 1632 Example 856 C24 H29 Cl N4 O3 457  10.3* 36 1633 Example 857 C23 H29 Cl N4 O3 445  10.9* 39 1634 Example 858 C23 H29 Cl N4 O3 445  8.6* 31 1635 Example 859 C22 H26 Cl2 N4 O2 449  11.0* 39 1636 Example 860 C23 H26 Cl N5 O2 440  9.2* 33 1637 Example 861 C22 H27 Cl N4 O s 431 13.3 62 1638 Example 862 C23 H29 Cl N4 O s 445 15.3 69 1639 Example 863 C23 H29 Cl N4 O2 S 461 14.7 64 1640 Example 864 C23 H29 Cl N4 O2 S 461 13.1 57 1641 *Yield of TFA salt.

Example 1642 Preparation of 1-(4-Chlorobenzyl)-4-[{N-(3-ethoxybenzoyl)-p-phenylalanyl}aminomethyl]piperidine (Compound No. 2091).

A solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (100 mg) in CHCl₃ (3 mL) was treated with Et₃N (0.090 mL), N-(tert-butoxycarbonyl)-p-phenylalanine (122 mg), EDCI (89 mg) and HOBt (62 mg). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was washed with 1 N aqueous NaOH solution (2 mL×2) and brine (2 mL). The organic layer was dried and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(tert-butoxycarbonyl)-p-phenylalanyl}aminomethyl]piperidine.

The resulting 1-(4-chlorobenzyl)-4-[{N-(tert-butoxycarbonyl)-p-phenylalanyl}aminomethyl]piperidine was dissolved in methanol (5 mL) and 4 N HCl in dioxane (1.5 mL) was added. The solution was stirred at room temperature for 19 h and concentrated.

A solution of the resulting material and 3-ethoxybenzoic acid (80 mg, 0.48 mmol) in CHCl₃, (1 ml)was treated with Et₃N (0.090 mL), EDCI (90 mg) and HOBt (68 mg). The reaction mixture was stirred at room temperature for 11 h. The reaction mixture was washed with 1 N aqueous NaOH solution (1.5 mL×2) and brine (1.5 mL). The organic layer was dried and concentrated. Column chromatography (SiO₂, CH₂Cl₂/MeOH 95:5) afforded 1-(4-chlorobenzyl)-4-[{N-(3-ethoxybenzoyl)-p-phenylalanyl}aminomethyl]piperidine (Compound No. 2091) (183.5 mg, 82%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 534.0 (M⁺+H, C₃H₃₆ClN₃O₃).

Examples 1643-1657.

The compounds of this invention were synthesized pursuant to methods of Example 1642 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 32.

TABLE 32 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 2092 C33 H37 Cl N4 O3 572.8 152.9 64 1643 Example 2093 C27 H36 Cl N3 O3 S 518.0 177.4 82 1644 Example 2094 C29 H34 Cl N3 O3 S 539.9 164.4 73 1645 Example 2095 C28 H38 Cl N3 O3 500.0 139.1 66 1646 Example 2096 C31 H42 Cl N3 O3 540.0 161.7 71 1647 Example 2097 C27 H36 Cl N3 O3 485.8 157.8 78 1648 Example 2098 C31 H35 Cl2 N3 O3 567.9 172.2 72 1649 Example 2099 C30 H34 Cl N3 O3 519.8 144.7 66 1650 Example 2100 C32 H38 Cl N3 O4 564.0 181.5 77 1651 Example 2101 C38 H42 CI N3 O4 639.9 192.3 72 1652 Example 2103 C33 H40 Cl N3 O4 577.8 159.9 66 1653 Example 2104 C28 H36 Cl N3 O5 530.1 99.7 45 1654 Example 2115 C27 H36 Cl N3 O3 486.2 122.9 60 1655 Example 2116 C28 H38 Cl N3 O3 500.1 118.3 57 1656 Example 2117 C28 H34 Cl N5 O3 524.1 98.3 45 1657

Reference Example 29 Preparation of 1-(tert-Butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine.

N-{3-(Trifluoromethyl)benzoyl}glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and Et₃N (1.72 g) were added to a solution of 1-(tert-butoxycarbonyl)-4(aminomethyl)piperidine (4.03 g) in dry CH₂Cl₂ (200 mL). The reaction mixture was stirred at 25° C. for 20 h. H₂O (100 mL) was added to the reaction mixture and the mixture was extracted with CH₂Cl₂ (2×50 mL). The combined extracts were washed with H₂O (2×50 mL), brine (50 mL) and dried (MgSO₄). The solvent was removed under reduced pressure to afford an yellow oil which was purified by column chromatography (Si₂, 70% EtOAc-hexane) to give 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (6.39 g, 85%): ¹H-NMR (CDCl₃, 300 MHz) δ 1.4 (s, 9 H), 1.0-1.8 (m, 5 H), 2.6-2.8 (m, 2 H), 3.15-3.3 (m, 2 H), 4.0-4.3 (m, 4 H), 6.6-6.7 (m, 1 H), 7.64 (s, 1 H, 7.60 (dd, 1 H, J=7.2, 7,2 Hz), 7.79 (d, 1 H, J=7,2 Hz), 8.0 (d, 1 H, J=7.2 Hz), 8.11 (s, 1 H); The purity was determined by RPLC/MS (97%); ESI/MS m/e 444.3 (M⁺+H, C₂₁H₂₈F₃N₃O₄)

Reference Example 30 Preparation of 4-[{N-(3-(Trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine.

A solution of 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (2.29 g, 5.16 mmol) in CH₃OH (40 mL) was treated with 1 N HCl-Et₂O (55 mL). The reaction mixture was stirred at 25° C. for 15 h and the solvent was removed under reduced pressure. 2 N aqueous NaOH solution (100 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine and dried (K₂CO₃). The solvent was removed under reduced pressure to afford a white solid which was purified by column chromatography (SiO₂, CH₃OH/CH₂Cl₂/EtN=7/6/1)) to give 4-[{N-3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (1.27 g, 72%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 344.1 (M⁺+H, Cl₁₆H₂₀F₃N₃O₃)

Example 1658 Preparation of 1-{3-(Trifluoromethoxy)benzyl}-4-[{(N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 927).

A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (19.9 mg, 0.058 mmol) in CH₃CN (1.0 mL) and (piperidinomethyl)polystyrene (55 mg, 2.7 mmol base/gresin) were added to a solution of 3-(trifluoromethoxy)benzyl bromide (12.3 mg, 0.048 mmol) in CH₃CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2.5 h. Phenyl isocyanate (6.9 mg, 0.048 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (20 mL). Product was eluted off using 2 N NH₃ in CH₃OH (6 mL) and concentrated to afford 1-{3-(trifluoromethoxy)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 927) (22.8 mg, 91%) as a pale yellow oil: The purity was determined by RPLC/MS (99%); ESI/MS m/e 518.1 (M⁺+H, C₂₄H_(26F) ₆N₃O₃)

Examples 1659-1710.

The compounds of this invention were synthesized pursuant to methods of Example 1658 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 33.

TABLE 33 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 875 C23 H26 F3 N3 O2 434 6.3 40 1659 Example 876 C23 H25 Br F3 N3 O2 512 4.3 23 1660 Example 877 C24 H25 F3 N4 O2 459 11.3 68 1661 Example 878 C23 H25 F3 N4 O4 479 8.3 48 1662 Example 884 C25 H29 F3 N4 O3 491 10.8 61 1663 Example 885 C24 H28 F3 N3 O4 S 512 9.0 49 1664 Example 886 C23 H25 F4 N3 O2 452 12.7 78 1665 Example 887 C24 H25 F6 N3 O2 502 13.9 77 1666 Example 888 C23 H26 F3 N3 O3 450 11.5 71 1667 Example 889 C29 H30 F3 N3 O2 510 12.4 68 1668 Example 890 C27 H28 F3 N3 O2 484 12.0 69 1669 Example 891 C23 H24 Cl2 F3 N3 O2 502 11.4 63 1670 Example 892 C24 H28 F3 N3 O3 464 11.7 70 1671 Example 893 C24 H26 F3 N5 O5 522 13.9 74 1672 Example 894 C26 H32 F3 N3 O3 492 11.3 64 1673 Example 895 C24 H28 F3 N3 O2 448 4.8 30 1674 Example 896 C24 H25 F3 N4 O2 459 17.5 quant 1675 Example 897 C24 H26 F3 N3 O4 478 9.2 57 1676 Example 898 C24 H26 F3 N3 O4 478 8.9 55 1677 Example 899 C24 H28 F3 N3 O3 464 13.7 82 1678 Example 900 C25 H28 F3 N3 O4 492 18.6 quant 1679 Example 901 C29 H30 F3 N3 O2 510 13.7 75 1680 Example 902 C23 H24 F3 N5 O6 524 12.6 67 1681 Example 903 C25 H30 F3 N3 O4 494 14.0 79 1682 Example 906 C25 H30 F3 N3 O2 462 11.2 67 1683 Example 907 C31 H34 F3 N3 O2 538 19.6 75 1684 Example 908 C30 H31 F3 N4 O3 553 30.4 76 1685 Example 909 C30 H31 F3 N4 O3 553 12.6 63 1686 Example 910 C23 H24 Cl2 F3 N3 O2 502 11.0 61 1687 Example 911 C23 H25 Cl F3 N3 O2 468 20.2 89 1688 Example 912 C23 H24 Br2 F3 N3 O2 590 20.2 95 1689 Example 913 C24 H28 F3 N3 O3 464 12.6 76 1690 Example 914 C30 H32 F3 N3 O3 540 13.9 72 1691 Example 915 C24 H28 F3 N3 O3 464 8.3 25 1692 Example 916 C22 H25 F3 N4 O2 435 2.5  8 1693 Example 917 C22 H25 F3 N4 O2 435 2.7  9 1694 Example 918 C26 H30 F3 N3 O4 506 3.9 22 1695 Example 919 C24 H28 F3 N3 O2 448 15.9 99 1696 Example 920 C24 H25 F6 N3 O3 518 20.3 81 1697 Example 921 C27 H28 F3 N3 O2 484 15.5 89 1698 Example 922 C20 H26 F3 N3 O2 398 7.3 51 1699 Example 923 C29 H29 Cl F3 N3 O2 544 12.5 48 1700 Example 928 C24 H25 F6 N3 O3 518 21.4 86 1701 Example 929 C24 H28 F3 N3 O2 S 480 23.7 quant 1702 Example 930 C24 H28 F3 N3 O2 448 21.3 99 1703 Example 931 C24 H25 F3 N4 O2 459 21.4 97 1704 Example 932 C23 H24 Cl F3 N4 O4 513 15.6 63 1705 Example 933 C24 H28 F3 N3 O2 448 16.6 77 1706 Example 934 C22 H25 F3 N4 O2 435 18.0 43 1707 Example 935 C23 H25 F3 N4 O4 479 15.1 65 1708 Example 936 C23 H25 F3 N4 O4 479 15.4 67 1709 Example 1615 C24 H25 F6 N3 O2 S 534.2 26.3 99 1710

Example 1711 Preparation of 1-{4-(Dimethylamino)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 937).

A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.058 mmol) in CH₃OH (1.0 ml) and NaBH₃CN (16.5 mg) were added to a solution of 4-(dimethylamino)benzaldehyde (30.4 mg, 0.204 mmol) in 5 % CH₃COOH/CH₃OH (1.0 mL). The reaction mixture was stirred at 60° C. for 19 h. The solvent was evaporated to afford a solid. CH₃CN (2.0 mL) and phenyl isocyanate (6.9 mg, 0.048 mmol) were added to the solid and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (20 mL). Product was eluted using 2 N NH₃—CH₃OH (6 mL) and the eluant was concentrated to afford 1-(4-(dimethylamino)benzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 937) as a pale yellow oil (13.5 mg, 49%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 477.3 (M⁺+H, C₂₅H₃₁F₃N₄O₂).

Examples 1712-1729.

The compounds of this invention were synthesized pursuant to methods of Example 1711 using the corresponding reactant respectively. Preparative TLC (SiO₂), if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 34.

TABLE 34 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 879 C24 H26 F3 N3 O4 478 13.0 62 1712 Example 880 C24 H26 F3 N3 O4 478 16.3 78 1713 Example 881 C23 H25 Br F3 N3 O2 512 11.4 51 1714 Example 882 C29 H30 F3 N3 O3 526 13.4 58 1715 Example 883 C23 H25 Cl F3 N3 O2 468 7.9 39 1716 Example 904 C23 H26 F3 N3 O3 450 3.3 17 1717 Example 905 C21 H23 F3 N4 O4 S 485 27.7 98 1718 Example 938 C23 H24 Cl F4 N3 O2 486 8.6 30 1719 Example 939 C23 H24 Cl F3 N4 O4 513 11.0 37 1720 Example 940 C23 H26 F3 N3 O3 450 5.5 21 1721 Example 941 C24 H24 Cl F6 N3 O2 536 11.2 36 1722 Example 987 C30 H32 F3 N3 O2 524 17.5 76 1723 Example 1449 C25 H30 F3 N3 O2 462 21.6 80 1724 Example 1450 C26 H32 F3 N3 O2 476 23.5 85 1725 Example 1452 C27 H35 F3 N4 O2 505 5.1 17 1726 Example 1453 C26 H32 F3 N3 O3 492 22.0 77 1727 Example 1454 C25 H30 F3 N3 O3 478 21.4 77 1728 Example 1456 C25 H28 F3 N3 O4 492 23.8 83 1729

Example 1730 Preparation of 1-{3-Hydroxy-4-rethoxybenzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1452).

To a solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.058 mmol) and 3-hydroxy-4-methoxybenzaldehyde (33 mg) in 5% CH₃COOH/CH₃OH (1 mL) was added NaBH₃CN (16.5 mg)in 5% CH₃COOH/CH₃OH (1.0 mL). The reaction mixture was stirred at 60° C. for 15 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (15 mL). Product was eluted using 2 N NH₃—CH₃OH (5 mL) and the eluant was concentrated to afford 1-{3-hydroxy-4-methoxybenzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1452) (25.8 mg, 92%): The purity was determined by RPLC/MS (91%); ESI/MSm/e 480 (M⁺+H, C₂₄H₂₈F₃N₃O₄).

Examples 1731-1733.

The compounds of this invention were synthesized pursuant to methods of Example 1730 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 35.

TABLE 35 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1731 1455 C24 H28 F3 N3 O4 480 24.0 86 Example 1732 1647 C27 H34 F3 N3 O2 490.2 23.6 96 Example 1733 1649 C26 H32 F3 N3 O2 476.2 23.1 97

Example 1734 Preparation of 1-(4-Benzylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 926).

A solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) in CHCl₃ (1.0 mL) and (piperidinomethyl)polystyrene (54 mg, 2.7 mmol base/g resin) were added to a solution of 4-(benzyl)benzyl alcohol (8.7 mg, 0.044 mmol) in CHCl₃ (1.0 mL). The reaction mixture was stirred at 25° C. for 15 h. A solution of 4[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (15.1 mg, 0.044 mmol) in CH₃CN (1.0 mL) and KI (2 mg) were added to the reaction mixture and the mixture was stirred at 65° C. for 5 h. Phenyl isocyanate (5.2 mg) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (20 mL). Product was eluted off using 2 N NH₃ in CH₃OH (6 mL) and concentrated to afford 1-(4-benzylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 926) as a pale yellow oil (5.6 mg, 29%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 524.1 (M⁺+H, C₃₆H₃₂F₃N₃O₂).

Reference Example 31 Preparation of 4-[{(N-(Benzyloxycarbonyi)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine.

A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol) in CH₂Cl₂ (80 mL) was treated with Et₃N (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol). After the reaction mixture was stirred at room temperature for 15 h, 2 N aqueous NaOH solution (100 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, ethyl acetate) afforded the desired 4-[{(N-(Benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (6.27 g, 94%) as an amorphous solid.

Reference Example 32 Preparation of 4-{(Glycylamino)methyl}-1-(text-butoxycarbonyl)piperidine.

A solution of 4-[{(N-(benzyloxycarbonyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (6.26 g, 15.4 mmol) in methanol (100 mL) was hydrogenated at 1 atm in the presence of 5% palladium on charcoal (620 mg) at room temperature for 7 h. The catalyst was removed by filtration through Celite and the combined filtrate was concentrated to afford 4-{(glycylamino}methyl-1-(tert-butoxycarbonyl)piperidine (3.84 g, 92 %) as a solid.

Reference Example 33 Preparation of 4-[{(N-(2-Amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine.

A solution of 4-{(glycylamino}methyl)-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol) in CH₂Cl₂ (25 mL) was treated with Et₃N (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol). After the reaction mixture was stirred at room temperature for 3 h, 2 N aqueous NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, ethyl acetate) afforded the desired 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]I-1-(tert-butoxycarbonyl)piperidine (1.63 g, 78%) as a solid.

Reference Example 34 Preparation of 4-[{(N-(2-Amino-5-chlorobenzoyl)glycyl)amino}methyl]piperidine.

To a solution of 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 3.84 mmol) in methanol (20 mL) was added 4 N HCl in dioxane (9.5 mL). The solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodium sulfate, filtered and concentrated to give 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]piperidine (1.19 g, 95%): ¹H NMR (CDCl₃, 270 MHz) δ 1.10-1.76 (m, 4 H), 2.55 (td, J=2.4 and 12.2 Hz, 2 H), 3.00-3.10 (m, 2 H), 3.17 (t, J=6.2 Hz, 2 H), 3.48 (s, 2 H), 4.03 (d, J=4.9 Hz, 2 H), 5.50 (br. s, 2 H), 6.11-6.23 (m, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.85-7.02 (m, 1 H), 7.15 (dd, J=2.7 and 8.8 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H); ESI/MS m/e 325.2 (C₁₅H₂₁ClN₄O₂).

4-[{(N-(2-Amino-5-bromobenzoyl)glycyl)amino}methyl]piperidine was also synthesized pursuant to methods of Reference Examples 32 and 33 using the corresponding reactant: 951 mg, 64% (2 steps). ESI/MS m/e 369.2 (C₁₅H₂₁BN₄O₂)

Example 1735 Preparation of 4-[{(N-(2-(tert-Butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]-1-(4-chlorobenzyl)piperidine.

A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine dihydrochloride (738 mg, 2 mmol) in CH₂Cl₂ (20 mL) was treated with Et₃N (1.1 mL, 8 mmol), 2-(tert-butoxycarbonylamino)-4,5-difluorobenzoic acid (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol). After the reaction mixture was stirred at room temperature for 14 h, 0.6 N aqueous NaOH solution (50 mL) was added, and the mixture was extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, ethyl acetate then ethyl acetate/methanol=92/8) afforded the desired 4-[{(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]-1-4-chlorobenzyl)piperidine (1.01 g, 92%): ESI/MS m/e 551.3 (M⁺+H, C₂₃-H₃₃ClF₂N₄O₄).

4-[{(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzo)glycyl)amino}methyl]-1-(4-chlorobenzyl)piperidine was also prepared pursuant to the above method using the corresponding reactant: 3.03 g, 82%; ESI/MS m/e 583.2 (M⁺+H, CB₂₈H₃₄ClF₃N₄O₄).

Reference Example 35 Preparation of 4-[{(N-(2-Amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine.

A suspension of 1-(4-chlorobenzyl)-4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine (447 mg, 0.93 mmol) and Pd(OH)₂ (60 mg, 0.23 mmol) in 5% HCO₂H/methanol (10 mL) was stirred at 50° C. for 14 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 1 N aqueous NaOH solution (15 mL) and the mixture was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO₂, AcOEt/MeOH/Et₃N=70/25/5) gave 4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl ]piperidine (284 mg, 86%): ESI/MS m/e 359.0 (M⁺+H, Cl₁₆H₂₁F₃N₄O₂).

4-[{(N-(2-Amino-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine, 4-[{N-(2-(tert-Butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine, 4-[{(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine, and 4-[{(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine were also prepared pursuant to the above method using the corresponding reactant, respectively.

4-[{(N-(2-amino-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine: 564 mg, 89%; ESI/MS m/e 327.2 (M⁺+H, Cl₁₅ H₂₀F₃N₄O₂).

4-[{N-(2-(tert-Butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine: quant; ¹H NMR (CDCl₃, 400 MHz) δ 1.10-1.25 (m, 2 H), 1.45-1.73 (m, 3 H), 1.51 (s, 9 H), 2.53-2.64 (m, 2 H), 3.04-3.13 (m, 2 H), 3.22 (t, J=6.3 Hz, 2 H), 4.09 (d, J=4.6 Hz, 2 H), 5.91 (br. s, 1 H), 7.08 (br. s., 1 H), 7.32 (d, J=9.0 Hz, 1 H), 7.38 (s, 1 H), 8.43 (d, J=9.0 Hz, 1 H).

4-[{(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine: 310 mg, 40%; ESI/MS m/e 427.3 (M⁺+H, C₂₀H₂₃F₂N₄O₄).

4-[{(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine: 1.35 g, 57; ESI/MS m/e 459.3 (M⁺+H, C₂₁H₂₆F₃N₄O₄).

Example 1736 Preparation of 4-[{-(2-Amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compound No. 1429) and 1-(4-Ethoxybenzyl)-4-[{N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 1433).

Sodium cyanoborohydride (140 mmol) in methanol (0.4 mL) was added to a mixture of 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (0.10 mmol), 4-ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL), and methanol (1.6 mL). The reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (20 mL). Product was eluted using 2 N NH₃ in CH₃OH (6 mL) and concentrated. Preparative TLC (SiO₂, AcOEt/CH3OH 5:1) afforded 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-ethoxybenzyl) (Compound No. 1429) and 1-(4-ethoxybenzyl)-4-[{N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 1433).

Compound No. 1429: 4.5 mg, 20%: The purity was determined by RPLC/MS (95%); ESI/MS m/e 459.2 (M⁺+H, C₂₄H₃₁ClN₄O₄).

Compound No. 1433: 8.4 mg, 28%: The purity was determined by RPLC/MS (98%); ESI/MS m/e 543.2 (M⁺+H, C₃₃H₄₁ClN₄O₄).

Examples 1737-1779.

The compounds of this invention were synthesized pursuant to methods of Example 1736 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 36.

TABLE 36 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1430 C24 H29 Cl N4 O4 473.0 3.1 13 1737 Example 1431 C24 H31 Br N4 O3 505.2 5.8 23 1738 Example 1432 C24 H29 Br N4 O4 517.0 4.1 16 1739 Example 1434 C33 H41 Br N4 O6 637.2 9.7 30 1740 Example 1435 C24 H31 Cl N4 O2 443.2 9.7 44 1741 Example 1436 C25 H33 Cl N4 O2 457.2 12.5 55 1742 Example 1437 C25 H33 Cl N4 O3 473.2 9.4 40 1743 Example 1438 C24 H31 Br N4 O2 489.2 5.9 24 1744 Example 1439 C25 H33 Br N4 O2 503.2 15.2 61 1745 Example 1440 C25 H33 Br N4 O3 519.2 11.0 43 1746 Example 1441 C23 H29 Br N4 O2 S 507.2 9.3 37 1747 Example 1442 C33 H41 Cl N4 O2 561.4 6.8 24 1748 Example 1443 C35 H45 Cl N4 O2 589.4 9.8 33 1749 Example 1444 C35 H45 Cl N4 O4 621.4 9.4 30 1750 Example 1445 C33 H41 Br N4 O2 605.2 6.5 21 1751 Example 1446 C35 H45 Br N4 O2 635.2 10.7 34 1752 Example 1447 C35 H45 Br N4 O4 665.4 12.4 37 1753 Example 1448 C31 H37 Br N4 O2 S2 643.2 7.6 24 1754 Example 1457 C24 H32 Cl N5 O2 458.2 4.5 20 1755 Example 1458 C23 H29 Cl N4 O4 461.2 6.0 26 1756 Example 1459 C24 H32 Br N5 O2 504.0 6.8 27 1757 Example 1460 C23 H29 Br N4 O4 505.0 8.0 32 1758 Example 1461 C31 H37 Cl N4 O6 597.2 5.9 20 1759 Example 1462 C31 H37 Br N4 O6 643.2 6.0 19 1760 Example 1514 C26 M36 Cl N5 O2 486.2 5.5 23 1761 Example 1515 C23 H29 Cl N4 O4 463.0 5.8 25 1762 Example 1516 C26 H36 Br N5 O2 530.2 4.2 16 1763 Example 1517 C23 H29 Br N4 O4 505.0 6.5 26 1764 Example 1518 C31 H37 Cl N4 O6 597.2 4.3 14 1765 Example 1519 C31 H37 Br N4 O6 641.2 5.3 17 1766 Example 1570 C23 H29 Cl N4 O2 S 461.0 2.7 12 1767 Example 1571 C31 H37 Cl N4 O2 S2 597.2 4.9 16 1768 Example 1651 C37 H49 Br N4 O2 663.2 5.5 17 1769 Example 1652 C26 H35 Br N4 O2 515.2 6.0 23 1770 Example 1653 C35 H45 Br N4 O2 633.2 5.0 16 1771 Example 1654 C25 H33 Br N4 O2 501.0 6.2 25 1772 Example 1655 C37 H49 Cl N4 O2 617.4 5.6 18 1773 Example 1656 C26 H35 Cl N4 O2 471.2 5.9 25 1774 Example 1657 C35 H45 Cl N4 O2 589.2 4.6 16 1775 Example 1658 C25 H33 Cl N4 O2 457.2 5.3 23 1776 Example 1785 C26 H33 F3 N4 O2 491.2 4.7 12.8 1777 Example 1786 C25 H29 F3 N4 O3 491.2 3.7 10.1 1778 Example 1804 C25 H32 F2 N4 O2 459.2 3.3 9.6 1779

Example 1780 Preparation of 4-[{N-(2-Amino-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compound No. 1903).

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxy)benzcylglycyl}aminomethyl]piperidine (0.050 mmol), 4-isopropylbenzaldehyde (0.060 mmol), NaBH₃CN (0.15 mmol), and methanol (1.3 mL) was added acetic acid (0.050 mL). The reaction mixture was stirred at 60° C. for 8 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (10 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL) and the solution was stirred overnight at room temperature. Concentration and preparative TLC gave 4-[{N-(2-amino-5-trifluoromethoxybenzoyol)glycyl}aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compound No. 1903) (6.6 mg, 26%): The purity was determined by RPLC/MS (93%) ESI/MS m/e 507 (M⁺+H, C₂₆H₃₃F₃N₄O₃).

Examples 1781-1783.

The compounds of this invention were synthesized pursuant to methods of Example 1780 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 37.

TABLE 37 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1781 1904 C26 H33 F3 N4 O3 507 9.6 37.9 Example 1782 1917 C25 H31 F3 N4 O5 525.2 1.2 3.1 Example 1783 1918 C24 H29 F3 N4 O4 495.2 2.8 7.5

Example 1784 Preparation of 4-[{-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052).

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH₃CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×3). Product was eluted off using 2 N NH₃ in CH₃OH (5 ml) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL: and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M⁺+H, C₂₄H₂₉BrF₂N₄O₃).

Examples 1785-1792.

The compounds of this invention were synthesized pursuant to methods of Example 1784 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 38.

TABLE 38 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1785 2053 C30 H34 F2 N4 O4 553.4 12.7 46 Example 1786 2054 C27 H30 F2 N4 O3 497.2 13.7 55 Example 1787 2055 C23 H28 F2 N4 O4 463.2 10.1 44 Example 1788 2056 C22 H24 Br F3 N4 O2 515.2 7.7 30 Example 1789 2057 C23 H27 Br F2 N4 O3 527.0 8.6 33 Example 1790 2058 C24 H30 F2 N4 O4 477.2 6.4 27 Example 1791 2059 C28 H30 F2 N4 O3 509.4 6.7 26 Example 1792 2060 C25 H32 F2 N4 O5 507.2 7.2 28

Example 1793 Preparation of 4-[{-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compound No. 2065).

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 3,4-diethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH₃CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material were added dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.125 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compound No. 2065) (21.2 mg, 84%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 505.2 (M⁺+H, C₂₆H₃₄F₂N₄O₄).

Examples 1794-1808.

The compounds of this invention were synthesized pursuant to methods of Example 1793 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 39.

TABLE 39 Com- pound Molecular Formula ESI/MS Yield Yield No. m/e (mg) (%) Example 1794 2061 C23 H27 F3 N4 O2 449.2 12.6 56 Example 1795 2062 C23 H27 F3 N4 O3 465.2 19.7 85 Example 1796 2063 C25 H32 F2 N4 O4 491.2 19.8 81 Example 1797 2064 C22 H24 Br F3 N4 O2 515.2 17.5 68 Example 1798 2066 C29 H32 F2 N4 O3 523.2 18.0 69 Example 1799 2067 C26 H34 F2 N4 O2 473.2 21.9 93 Example 1800 2068 C22 H24 Cl F3 N4 O2 469.2 11.2 48 Example 1801 2069 C24 H30 F2 N4 O3 461.4 20.2 88 Example 1802 2070 C23 H27 Br F2 N4 O3 527.2 17.7 67 Example 1803 2071 C24 H30 F2 N4 O4 477.2 10.9 46 Example 1804 2072 C25 H32 F2 N4 O3 475.2 19.3 81 Example 1805 2073 C29 H32 F2 N4 O3 523.2 22.8 87 Example 1806 2074 C29 H32 F2 N4 O4 539.2 22.5 84 Example 1807 2075 C23 H27 F3 N4 O3 465.2 14.9 64 Example 1808 2076 C22 H24 F4 N4 O2 453.2 21.9 97

Example 1809 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compound No. 2106).

To a mixture of 4-[{(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 2-hydroxy-3-methylbenzaldehyde (25 mmol), methanol (1.0 mL), and acetic acid (0.040 mL) was added NaBH₃CN (0.40 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (5 mL), and concentrated. The residue was dissolved in methanol (2 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH3 in CH₃OH (5 mL) and concentrated. Preparative TLC afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl--1-(2-hydroxy-3-methylbenzyl)piperidine (Compound No. 2106): The purity was determined by RPLC/MS (97%); ESI/MS m/e 447.0 (M⁺+H, C₂₃H₂₈F₂N₄O₃).

Examples 1810-1823.

The compounds of this invention were synthesized pursuant to methods of Example 1809 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 40.

TABLE 40 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) Example 2077 C22 H25 Cl F2 N4 O3 467.2  3.7 16 1810 Example 2078 C24 H30 F2 N4 O4 477.2  1.9  8 1811 Example 2079 C30 H34 F2 N4 O4 553.4  4.8 17 1812 Example 2080 C22 H25 Cl F2 N4 O3 467.2 13.5 58 1813 Example 2081 C22 H25 Cl F2 N4 O3 467.2 13.8 59 1814 Example 2082 C23 H28 F2 N4 O4 463.2  9.6 42 1815 Example 2105 C23 H28 F2 N4 O4 463.2 ND ND 1816 Example 2106 C23 H28 F2 N4 O3 447.0 ND ND 1817 Example 2107 C20 H23 Br F2 N4 O2 S 503.1 ND ND 1818 Example 2108 C25 H28 F2 N4 O2 S 487.2 ND ND 1819 Example 2109 C20 H23 Br F2 N4 O3 487.0 ND ND 1820 Example 2110 C22 H28 F2 N4 O3 435.1 ND ND 1821 Example 2111 C22 H24 Cl F3 N4 O2 469.0 ND ND 1822 Example 2112 C24 H29 Br F2 N4 O4 557.0 ND ND 1823 ND: Not determined.

Example 1824 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compound No. 2114).

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH₃CN (0.50 mmol) in methanol (1.0 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃, in CH₃OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=2/1 (2 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=2/1 (6 mL), and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH, in CH₃OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine.

A mixture of 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine prepared above, 5% palladium-activated carbon (15 mg), and methanol (2 mL) was stirred under a hydrogen atmosphere at room temperature for 4 h. The Pd catalyst was filtered off through Celite and the filtrate was concentrated. Preparative TLC (SiO₂, ethyl acetate/MeOH=3/1) gave 4-{(N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compound No. 2114) (2.9 mg, 13%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 446.1 (M⁺+H, C₂₃, H_(29F) ₂N₅O₂).

Example 1825 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methoxybenzyl) piperidine (Compound No. 2113).

The titled compound, 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-methoxybenzyl)piperidine (Compound No. 2113), was synthesized pursuant to methods of Example 1824 using the corresponding reactant: 4.6 mg, 20% yield; ESI/MS m/e 462.2 (M⁺+H, C₂₃H₂₉F₂N₅O₃).

Example 1826 Preparation of 1-(3-Amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine.

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.35 mmol), 4-hydroxy-3-nitrobenzaldehyde (1.22 mmol), methanol (3.8 mL), and acetic acid (0.175 mL) was added NaBH₃CN (1.58 mmol) in methanol (3.2 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH. Product was eluted off using 2 N NH in CH₃OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/metharol=5/1 (10 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzol)glycyl}aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine (175 mg, 87%).

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-hydroxy-3-notrobenzyl)piperidine prepared above, 10% palladium-activated carbon (45 mg), and methanol (5 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The Pd catalyst was filtered off and the filtrate was concentrated to afford 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (100 mg, 60%).

Example 1827 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydrxybenzil)piperidine (Compound No. 2141).

To a solution of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.035 mmol) in methanol (1 mL) was added 4 N HCl in dioxane (0.50 mL) and the solution was stirred at room temperature overnight. After the solution was concentrated, the residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH, in CH₃OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (Compound No. 2141) (17.6 mg, quant.): The purity was determined by RPLC/MS (85%); ESI/MS m/e 448.3 (M⁺+H, C₂₂H₂₇F₂N₅O₃).

Examples 182(1-1831.

The compounds of this invention were synthesized pursuant to methods of Examples 1826 and 1827 using the corresponding reactants respectively. Preparative TLC (SiO₂), if needed, afforded the desired material. The ESI/MS data and yields of last step are summarized in Table 41.

TABLE 41 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1828 2140 C23 H27 F2 N5 O4 476.3 6.7 28.4 Example 1829 2144 C24 H30 F3 N5 O3 494.2 18.7 82.0 Example 1830 2145 C23 H28 F3 N5 O3 480.3 19.8 63.7 Example 1831 2146 C24 H28 F3 N5 O4 508.3 13.5 81.7

Example 1832 Preparation of 1-(3-Amino-4-chlorobenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine.

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) was added NaBH₃CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH. Product was eluted off using 2 N NH; in CH₃OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5/1 (6 mL), and concentrated to give 4-[{I-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%): ESI/MS m/e 596.3 (M⁺+H).

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (121 mg, 0.20 mmol), 10% palladium-activated carbon (85 mg), ethyl acetate (10 mL), and methanol (1 mL) was stirred under a hydrogen atmosphere at room temperature for 19 h. The Pd catalyst was filtered off and the filtrate was concentrated to afford 1-(3-amino-4-chlorobenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (78 mg, 68%).

Example 1813 Preparation of 1-(3-Amino-4-chlorobenzyl)-4-[{N-(2-amino-4,5-difluorolenzoyl)glycyl}aminomethyl]piperidine (Compound No. 2142).

The titled compound, 1-(3-amino-4-chlorobenzyl)-4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 2142) was synthesized pursuant to method of Example 1832 using the corresponding reactant: 13.7 mg, 98%); The purity was determined by RPLC/MS (83%); ESI/MS m/e 466.2 (M⁺+H, C₂₂H₂₆ClF₂N₅O₂).

Example 1834 Preparation of 1-(3-Acetylamino-4-hydroxybenzyl)-4[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 2148).

To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH₃OH. Product was eluted off using 2 N NH₃ in CH₃OH and concentrated to give 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M⁺+H, C₂₉H₃₇F₂N₅O₆).

To a solution of 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine obtained above in methanol (1 mL) was added 4 N HCl in dioxane (0.50 mL) and the solution was stirred at room temperature overnight. After the solution was concentrated, the residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH₃ in CH₃OH (5 mL). Concentration and preparative TLC (SiO₂, AcOEt/MeOH=3:2) afforded 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 2148) (2.3 mg, 9.2%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 490.3 (M⁺+H, C₂₄H₂₉F₂N₅O₄).

Examples 1835-1839

The compounds of this invention were synthesized pursuant to methods of Examples 1826 and 1834 using the corresponding reactants respectively. The ESI/MS data and yields are summarized in Table 42.

TABLE 42 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1835 2143 C25 H29 F2 N5 O5 518.3 4.8 45 Example 1836 2147 C25 H31 F2 N5 O4 504.3 3.0 23 Example 1837 2154 C26 H32 F3 N5 O4 536.4 4.1 66 Example 1838 2155 C25 H30 F3 N5 O4 522.3 5.5 71 Example 1839 2156 C26 H30 F3 N5 O5 550.3 7.0 78

Example 1840 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine (Compound No. 2160)

To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (20.4 mg, 0.037 mmol), 37% HCHO solution (3.0 mg, 0.037 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH₃CN (7.0 mg) in methanol (0.2 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (8 mL) and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine.

To a solution of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-hydroxybenzyl)piperidine obtained above in methanol (1.0 mL) was added 4 N HCl in dioxane (1.0 mL) and the solution was stirred at room temperature for 3 h. After the solution was concentrated, the residue was dissolved in methanol (1 mL), loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH₃ in CH₃OH (8 mL). Concentration and preparative TLC (SiO₂) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine (Compound No. 2160) (3.4 mg, 20%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 462.4 (M⁺+H, C₂₃H₂₉F₂N₅O₃).

Examples 1841-1844

The compounds of this invention were synthesized pursuant to methods of Examples 1826 and 1840 using the corresponding reactants respectively. The ESI/MS data and yields are summarized in Table 43.

TABLE 43 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1841 2159 C24 H31 F2 N5 O3 476.3 7.6 48 Example 1842 2161 C23 H28 Cl F2 N5 O2 480.3 7.3 45 Example 1843 2162 C25 H32 F3 N5 O3 508.4 6.0 24 Example 1844 2163 C24 H30 F3 N5 O3 494.3 4.3 15

Example 1845 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compound No. 2130)

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-(bromomethyl)benzo[c]furazan (0.75 mmol), (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL), and chloroform (0.50 mL) was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting mat(rial were added chloroform (1.5 mL) and phenyl isocyanate (0.075 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH₃OH (5 mL×2). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH₃OH (5 mL×2), and eluted off using 2 N NH₃ in CH₃OH (5 mL). Concentration and preparative TLC (SiO₂, ethyl acetate/MeOH=5/1) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compound No. 2130) (3.6 mg, 16%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 459.3 (M⁺+H, C₂₂H₂₄F₂N₆O₃).

Example 1846 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,5-dimethylisoxazol-4-yl)piperidine (Compound No. 2131).

The titled compound, 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,5-dimethylisoxazol-4-yl)piperidine (Compound No. 2131), was synthesized pursuant to methods of Example 1845 using the corresponding reactant: 3.8 mg, 18% yield; ESI/MS m/e 436.2 (M⁺+H, C₂₁H₂₇F₂N₅O₃).

Example 1847 Preparation of 4-[{N-(2-Amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-{4-(trifluoromethylthio)benzyl}piperidine (Compound No. 1616)

A mixture of 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (16.2 mg, 0.050 mmol), 4(trifluoromethylthio)benzyl bromide (20.3 mg, 0.075 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 60° C. for 15 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH₃OH (15 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-{4-(trifluoromethylthio)benzyl}piperidine (Compound No. 1616) (21.9 mg, 85%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545.2 (M⁺+H, C₂₃H₂₆ClF₃N₄O₂S).

Example 1848-1868

The compound of this invention was synthesized pursuant to methods of Example 1847 using the corresponding reactant. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 44.

TABLE 44 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1617 C23 H26 Br F3 N4 O2 S 559.0 21.0 75 1848 Example 1777 C23 H25 Cl2 F3 N4 O2 517.0 16.3 63.0 1849 Example 1778 C24 H29 F3 N4 O2 463.2 9.5 41.1 1850 Example 1779 C24 H27 F3 N4 O4 493.2 12.7 51.6 1851 Example 1780 C23 H26 Br F3 N4 O2 527.0 16.4 62.2 1852 Example 1781 C23 H27 F3 N4 O3 465.2 10.0 28.7 1853 Example 1782 C25 H29 F3 N4 O2 475.2 12.2 34.3 1854 Example 1783 C24 H26 F3 N5 O2 474.2 17.2 48.4 1855 Example 1784 C23 H27 F3 N4 O2 449.2 11.3 33.6 1856 Example 1788 C25 H31 F3 N4 O2 477.2 10.0 42.0 1857 Example 1789 C24 H29 F3 N4 O3 479.2 10.0 27.9 1858 Example 1792 C24 H30 F2 N4 O2 445.2 5.9 26.5 1859 Example 1793 C22 H24 Cl2 F2 N4 O2 485.2 9.2 37.9 1860 Example 1794 C23 H28 F2 N4 O2 431.2 5.7 26.5 1861 Example 1795 C23 H26 F2 N4 O4 461.2 6.0 26.1 1862 Example 1796 C22 H25 Br F2 N4 O2 497.0 10.5 42.4 1863 Example 1797 C22 H26 F2 N4 O3 433.2 3.5 16.2 1864 Example 1798 C23 H28 F2 N4 O3 447.2 5.6 25.1 1865 Example 1799 C24 H28 F2 N4 O2 443.2 5.5 24.9 1866 Example 1800 C23 H25 F2 N5 O2 442.2 9.4 42.6 1867 Example 1801 C22 H26 F2 N4 O2 417.2 6.5 31.2 1868

Example 1869 Preparation of 4-[{N-(2-Amino-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]-1-(4-bromobenzyl)piperidine (Compound No. 1910).

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-bromobenzyl bromide (0.060 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl₃/CH₃OH (10 mL) and CH₃OH (10 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL), and the solution was stirred overnight at room temperature. Concentration and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethoxybenzoyl) glycyl}aminomethyl]-1-(4-bromobenzyl)piperidine (Compound No. 1910) (6.5 mg, 24%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545 (M⁺+H, C₂₃H₂₆BrF₃N₄O₃).

Examples 1870-1873

The compounds of this invention were synthesized pursuant to methods of Example 1869 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 45.

TABLE 45 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1911 C23 H25 Cl2 F3 N4 O3 533 10.6 39.7 1870 Example 1912 C23 H27 F3 N4 O4 481 12.5 52.0 1871 Example 1913 C25 H31 F3 N4 O3 493 7.5 30.5 1872 Example 1914 C24 H29 F3 N4 O3 479 11.0 46.0 1873

Example 1874 Preparation of 4-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(benz[d]imidazol-5-yl)piperidine (Compound No. 2186).

A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine (0.060 mmol), 1-(tert-butoxycarbonyl)-6-(bromomethyl)benz[d]imidazole (15.6 mg, 0.050 mmol), (piperidinomethyl)polystyrene (86 mg), and acetonitrile (2 mL) was stirred at 50° C. for 3 h. After cooling to room temperature, phenyl isocyanate (30 mg) was added and the mixture was stirred at room temperature for 1 h, loaded onto Varian™ SCX column and washed with CH₃OH (5 mL) and CHCl₃ (5 mL). Product was eluted using 2 N NH₃ in CH₃OH (3 mL) and concentrated.

The resulting material was dissolved into methanol (1 mL), and 4 N HCl in dioxane (1 mL) was added. The solution was stirred at room temperature overnight, loaded onto Varian™ SCX column and washed with CH₃OH and dichloromethane. Product was eluted using 2 N NH₃ in CH₃OH and concentrated. Preparative TLC (SiO₂, AcOEt/MeOH=3:1) afforded 4-[{N-(2-amino-5-trifluorobenzoyl)glycyl}aminomethyl]-1-(benz[d]imidazol-5-yl)piperidine (Compound No. 2186) (1.9 mg, 7.8%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 489.4 (M⁺+H, C₂₄H₂₇F₃N₆O₂).

Example 1875 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compound No. 2184)

To a mixture of 5-(hydroxymethyl)benzo[c]thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl)polystyrene (86 mg), and chloroform (1 mL) was added methanesulfonyl chloride (0.0042 mL) and the mixture was stirred at room temperature for 1.5 h. Acetonitrile (1 mL) and 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.060 mmol) was added and the reaction mixture was stirred at 50° C. for 3 h. After cooling to room temperature, phenyl isocyanate (30 mg) was added, and the mixture was stirred at room temperature for 1 h, loaded onto Varian™ SCX column and washed with CH₃OH (5 mL) and CHCl₃ (5 mL). Product was eluted using 2 N NH₃ in CH₃OH (3 mL) and concentrated.

The resulting material was dissolved into dichloromethane (1 mL), and 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane (1 mL) was added. The solution was stirred at room temperature for 5 h, loaded onto Varian™ SCX column and washed with CH₃OH and dichloromethane. Product was eluted using 2 N NH₃ in CH₃OH and concentrated. Preparative TLC (SiO₂, AcOEt/MeOH=3:1) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compound No. 2184) (1.3 mg, 5.5 %): The purity was determined by RPLC/MS (100%); ESI/MS m/e 475.2 (M⁺+H, C₂₂H₂₄F₂N₆O₂S).

Example 1876 Preparation of 4-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compound No. 2185)

The titled compound, 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compound No. 2185) was synthesized pursuant to methods of Example 1875 using the corresponding reactant: 7.2 mg, 28% yield; ESI/MS m/e 507.4 (M⁺+H, C₂₃H₂₅F₃N₆O₂S).

Example 1877 Preparation of 4-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compound No. 1919)

A mixture of 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl₃/CH₃OH (10 mL) and CH₃OH (10 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd-C (15 mg), and the mixture was stirred under H₂ at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compound No. 1919) (5.1 mg, 14%): The purity was determined by RPLC/MS (90%); ¹HNMR (400 MHz, CDCl₃) δ 1.09-1.32 (m, 4 H), 1.41-1.59 (m, 1 H), 1.66 (d, J=12.5 Hz, 2 H), 1.88 (t, J=11.5 Hz, 2 H), 2.82 (d, J=11.5 Hz, 2 H), 3.17 (t, J=6.5 Hz, 2 H), 3.42 (s, 2 H), 4.05 (d, J=5.5 Hz, 2 H), 4.85 (br s, 1 H), 5.92 (br s, 2 H), 6.25-6.36 (m, 1 H), 6.55-6.66 (m, 1 H), 6.70 (d, J=8.5 Hz, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 7.26 (s, 1 H), 7.42 (d, J=8.5 Hz, 1 H), 7.68 (s, 1 H); ESI/MS m/e 498.2 (M⁺+H, C₂₃H₂₇ClF₃N₅O₂).

Examples 1878 and 1879

The compounds of this invention were synthesized pursuant to methods of Example 1877 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 46.

TABLE 46 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1878 1920 C22 H26 Cl F2 N5 O2 466.2 3.5 10.0 Example 1879 1922 C23 H27 Cl F3 N5 O3 514.2 1.2 3.1

Example 1880 Preparation of 4-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(benz[d]oxazol-5-yl)piperidine (Compound No. 2188)

A solution of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethyl]piperidine (34.8 mg, 0.060 mmol), prepared pursuant to methods of Example 1826, in THF (2 mL) was treated with triethyl orthoformate (0.033 mL, 3.3 eq) and pyridinium p-toluenesulphonate (2 mg, 0.4 eq). The reaction mixture was stirred overnight under reflux. After cooling to room temperature, the mixture was concentrated. The residue was dissolved in AcOEt, loaded onto BondElut™ Si column, eluted off using ethyl acetate/methanol=4/1, and concentrated.

The resulting material was dissolved into AcOEt (1.5 mL), and 4 N HCl in dioxane (0.5 mL) was added. The solution was stirred at room temperature overnight, adjusted to pH 10 with 5 M NaOH aqueous solution, and extracted with AcOEt. The extract was concentrated and purified by PTLC (SiO₂, AcOEt/MeOH=4:1) to afford 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(benz[d]oxazol-5-yl)piperidine (Compound No. 2188) (1.6 mg, 5%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 490.3 (M⁺+H, C₂₄H₂₆F₃N₅O₃).

Example 1881 Preparation of 4-[{N-(2-Amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)piperidine (Compound No. 2190)

To a mixture of 1-(3-amino-4-hydroxy)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl) glycyl}aminomethyl]piperidine (22 mg, 0.040 mmol), NaHCO₃ (0.040 mmol), water (0.7 mL), and methanol (1.5 mL) was added phenyl chloroformate (0.046 mmol) and the mixture was stirred at room temperature for 3 h. A 1 N NaOH solution (0.040 mL) was added, and the reaction mixture was stirred for additional 1.5 h. The mixture was extracted with ethyl acetate and evaporated. The residue was dissolved in methanol, loaded onto Varian™ SCX column and washed with CH₃OH (5 mL×2). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated.

To the resulting material was added 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane (2 mL). The solution was stirred at room temperature for 2 h and evaporated. The residue was dissolved in methanol, loaded onto Varian™ SCX column and washed with CH₃OH (5 mL×2). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. Preparative TLC (SiO₂, AcOEt/MeOH=5:2) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)piperidine (Compound No. 2190) (4.1 mg, 22%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 474.2 (M⁺+H, C₂₃H₂₅F₂N₅O₄).

Examples 1882-1884

The compounds of this invention were synthesized pursuant to methods of Example 1881 using the corresponding reactant respectively (phenyl chlorothionoformate was used instead of phenyl chloroformate for preparation of Compounds 2192 and 2193). The ESI/MS data and yields are summarized in Table 47.

TABLE 47 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1882 2191 C24 H26 F3 N5 O4 506.3 3.1 10 Example 1883 2192 C23 H25 F2 N5 O3 S 490.2 6.9 35 Example 1884 2193 C24 H26 F3 N5 O3 S 522.2 3.6 11

Reference Example 36 Preparation of 4-[{N-(1-(9-Fuluorenylmethoxycarbonyl)piperidine-4-ylmethyl)carbamoylmethyl}aminomethyl]-3-methoxyphenyloxymethyl-polystyrene

To a solution of 1-(9-fuluorenylmethoxycarbonyl)-4-(glycylaminomethyl)piperidine hydrochloride (10 mmol) in DMF (65 mL) were added acetic acid (0.3 mL), sodium triacetoxyborohydride (1.92 g), and 4-formyl-3-(methoxyphenyloxymethyl)-polystyrene (1 mmol/g, 200 g). The mixture was shaken for 2 h and filtered. The resin was washed with MeOH, DMF, CH₂Cl₂, and methanol, and dried to afford the desired material.

Examples 1885-2000 General Procedure for Solid-Phase Synthesis of 4-Aminomethylpiperidines

To a mixture of the corresponding acid (1.6 mmol), HBTU (1.6 mmol), and DMF (6 mL) was added diisopropylethylamine (3.6 mmol), and the mixture was shaken for 2 min. 4-[{-(1-(9-fluorenylmethoxycarbonyl)piperidine-4-ylmethyl)carbamoylmethyl}aminomethyl]-3-methoxyphenyloxymethyl-polystyrene (0.4 mmol) was added and the mixture was shaken for 1 h and filtered. The resin was rinsed with DMF and CH₂Cl₂, and dried.

A mixture of the resulting resin, piperidine (3.2 mL), and DMF (12.8 mL) was shaken for 10 min and filtered. The resin was washed with DMF and CH₂Cl₂, and dried.

To the dry resin (0.05 mmol) was added a mixture of NaBH(OAc)₃ (0.25 mmol), AcOH (0.025 mL) and DMF (1 mL). The corresponding aldehyde (2.5 mmol) was added, and the mixture was shaken for 2 h, then filtered and washed with CH₃OH, 10% diisopropylethylamine in DMF, DMF, CH₂Cl₂, and CH₃OH. A mixture of the resin, water (0.050 mL), and trifluoroacetic acid (0.95 mL) was shaken for 1 h and filtered. The resin was washed with CH₂Cl₂ and CH₃OH. The filtrate and washings were combined and concentrated. The crude material was loaded onto Varian™ SCX column and washed with CH₃OH (15 mL). Product was eluted using 2 N NH₃ in CH₃OH (5 mL) and concentrated. Preparative TLC or HPLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 48.

TABLE 48 Com- ESI/ pound MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1923 C23 H25 Br F3 N3 O2 S 544 15.7 87 1885 Example 1924 C24 H28 F3 N3 O3 S 496 14.6 89 1886 Example 1925 C23 H25 F4 N3 O2 S 484 11.7 73 1887 Example 1926 C23 H24 F5 N3 O2 S 502 13.9 84 1888 Example 1927 C23 H26 F3 N3 O3 S 482 10.7 67 1889 Example 1928 C24 H26 F3 N3 O4 S 510 14.3 85 1890 Example 1929 C26 H30 F3 N3 O2 S 506 14.7 88 1891 Example 1930 C24 H28 F3 N3 O2 S2 512 14.4 85 1892 Example 1931 C25 H30 F3 N3 O2 S 494 14.3 88 1893 Example 1932 C25 H28 F3 N3 O3 S 509  7.1* 35 1894 Example 1933 C25 H30 F3 N3 O2 S 494 14.3 88 1895 Example 1934 C26 H32 F3 N3 O2 S 509 14.4 86 1896 Example 1935 C23 H25 F3 N4 O4 S 511 14.9 88 1897 Example 1936 C24 H28 F3 N3 O2 S 480 13.3 84 1898 Example 1937 C26 H32 F3 N3 O2 S 509 11.1 66 1899 Example 1938 C23 H27 Br2 N3 O2 538  5.3* 25 1900 Example 1939 C24 H30 Br N3 O3 488  5.0* 25 1901 Example 1940 C23 H27 Br F N3 O2 476  4.9* 25 1902 Example 1941 C23 H26 Br F2 N3 O2 494  6.1* 30 1903 Example 1942 C23 H28 Br N3 O3 474  1.7* 9 1904 Example 1943 C24 H28 Br N3 O4 502  6.6* 32 1905 Example 1944 C26 H32 Br N3 O2 498  7.0* 35 1906 Example 1945 C24 H30 Br N3 O2 S 504 11.1 67 1907 Example 1946 C25 H32 Br N3 O2 488  3.2* 16 1908 Example 1947 C25 H30 Br N3 O3 500  5.7 35 1909 Example 1948 C25 H32 Br N3 O2 486  4.9* 25 1910 Example 1949 C26 H34 Br N3 O2 500  6.7* 33 1911 Example 1950 C23 H27 Br N4 O4 503  5.0* 25 1912 Example 1951 C24 H30 Br N3 O2 472  5.1* 26 1913 Example 1952 C22 H24 Br2 F N3 O2 542 14.9 83 1914 Example 1953 C23 H27 Br F N3 O3 492 13.9 86 1915 Example 1954 C22 H24 Br F2 N3 O2 480 12.5 79 1916 Example 1955 C22 H23 Br F3 N3 O2 498 13.2 80 1917 Example 1956 C22 H25 Br F N3 O3 478  7.0 44 1918 Example 1957 C23 H25 Br F N3 O4 506  4.0* 20 1919 Example 1958 C25 H29 Br F N3 O2 502 14.6 88 1920 Example 1959 C23 H27 Br F N3 O2 S 508 13.1 78 1921 Example 1960 C24 H29 Br F N3 O2 490 13.8 85 1922 Example 1961 C24 H27 Br F N3 O3 504  2.7* 13 1923 Example 1962 C24 H29 Br F N3 O2 490 12.7 78 1924 Example 1963 C25 H31 Br F N3 O2 504 13.5 81 1925 Example 1964 C22 H24 Br F N4 O4 507 14.8 88 1926 Example 1965 C23 H27 Br F N3 O2 476 12.1 77 1927 Example 1966 C25 H31 Br F N3 O2 504 13.4 80 1928 Example 1967 C22 H26 Br F N4 O2 477  4.7* 20 1929 Example 1968 C23 H29 F N4 O3 429  6.9* 32 1930 Example 1969 C22 H27 F N4 O3 415  3.7* 17 1931 Example 1970 C23 H27 F N4 O4 443  5.4* 24 1932 Example 1971 C25 H31 F N4 O2 439  4.3* 20 1933 Example 1972 C23 H29 F N4 O2 S 445  6.2* 28 1934 Example 1973 C24 H31 F N4 O2 427  6.3* 29 1935 Example 1974 C24 H31 F N4 O2 427  4.9* 23 1936 Example 1975 C22 H26 F N5 O4 444  5.9* 27 1937 Example 1976 C23 H29 F N4 O2 413  6.7* 32 1938 Example 1977 C23 H26 F N5 O2 424  5.1* 24 1939 Example 1978 C25 H33 F N4 O2 441  6.3* 29 1940 Example 1979 C25 H30 F2 N4 O2 457  8.0* 35 1941 Example 1980 C24 H28 F2 N4 O3 459  6.0* 26 1942 Example 1981 C22 H25 F2 N5 O4 462  9.3* 41 1943 Example 1982 C23 H25 F2 N5 O2 442  6.0* 27 1944 Example 1983 C25 H32 F2 N4 O2 459  8.3* 37 1945 Example 1984 C22 H26 Br I N4 O2 585  9.7* 36 1946 Example 1985 C23 H29 I N4 O3 537  9.2* 36 1947 Example 1986 C22 H27 I N4 O3 523  5.8* 23 1948 Example 1987 C23 H27 I N4 O4 551  8.2* 32 1949 Example 1988 C25 H31 I N4 O2 547  6.7* 26 1950 Example 1989 C23 H29 I N4 O2 3 553  6.4* 25 1951 Example 1990 C24 H31 I N4 O2 535  7.2* 29 1952 Example 1991 C24 H29 I N4 O3 549  5.6* 22 1953 Example 1992 C24 H31 I N4 O2 535  6.2* 25 1954 Example 1993 C22 H26 I N5 O4 552  10.2* 40 1955 Example 1994 C23 H29 I N4 O2 521  7.5* 30 1956 Example 1995 C23 H26 I N5 O2 532  6.8* 27 1957 Example 1996 C25 H33 I N4 O2 549  7.1* 28 1958 Example 1997 C25 H33 I N4 O2 549  3.0* 12 1959 Example 1998 C22 H25 Br Cl N3 O2 478  7.6* 39 1960 Example 1999 C23 H28 Cl N3 O3 430  7.0* 39 1961 Example 2000 C22 H25 Cl F N3 O2 418 14.1 102 1962 Example 2001 C22 H26 Cl N3 O3 416  6.3* 36 1963 Example 2002 C23 H26 Cl N3 O4 444  7.1* 39 1964 Example 2003 C25 H30 Cl N3 O2 440 15.3 105 1965 Example 2004 C23 H28 Cl N3 O2 S 446  8.4* 45 1966 Example 2005 C24 H30 Cl N3 O2 428  7.4* 41 1967 Example 2006 C24 H30 Cl N3 O2 428 13.8 98 1968 Example 2007 C22 H25 Cl N4 O4 445 16.0 109 1969 Example 2008 C23 H28 Cl N3 O2 414 14.1 103 1970 Example 2009 C23 H25 Cl N4 O2 425 14.8 106 1971 Example 2010 C25 H32 Cl N3 O2 442 14.5 99 1972 Example 2011 C25 H32 Cl N3 O2 442 14.5 99 1973 Example 2012 C22 H24 Br2 Cl N3 O2 558  12.8* 58 1974 Example 2013 C23 H27 Br Cl N3 O3 508  8.6* 42 1975 Example 2014 C22 H25 Br Cl N3 O3 494  6.0* 30 1976 Example 2015 C23 H25 Br Cl N3 O4 522  8.4* 40 1977 Example 2016 C25 H29 Br Cl N3 O2 518 17.6 103 1978 Example 2017 C23 H27 Br Cl N3 O2 S 524 17.1 99 1979 Example 2018 C24 H29 Br Cl N3 O2 506 14.7 88 1980 Example 2019 C24 H27 Br Cl N3 O3 520  8.0* 38 1981 Example 2020 C24 H29 Br Cl N3 O2 506 14.7 88 1982 Example 2021 C22 H24 Br Cl N4 O4 523  12.0* 57 1983 Example 2022 C23 H27 Br Cl N3 O2 492  8.5* 42 1984 Example 2023 C23 H24 Br Cl N4 O2 503  6.3* 31 1985 Example 2024 C25 H31 Br Cl N3 O2 520  9.6* 46 1986 Example 2025 C25 H31 Br Cl N3 O2 520 15.0 87 1987 Example 2026 C22 H23 Br Cl F2 N3 O2 514 15.8 93 1988 Example 2027 C22 H26 Br2 N4 O2 537  10.7* 42 1989 Example 2028 C23 H29 Br N4 O3 489  8.5* 36 1990 Example 2029 C22 H27 Br N4 O3 475  7.5* 32 1991 Example 2030 C23 H27 Br N4 O4 503  6.8* 28 1992 Example 2031 C25 H31 Br N4 O2 499  6.2* 26 1993 Example 2032 C24 H29 Br N4 O3 501  8.9* 37 1994 Example 2033 C24 H31 Br N4 O2 487  9.1* 39 1995 Example 2034 C22 H26 Br N5 O4 504  6.4* 26 1996 Example 2035 C23 H29 Br N4 O2 473  6.5* 28 1997 Example 2036 C23 H26 Br N5 O2 484  6.3* 27 1998 Example 2037 C25 H33 Br N4 O2 501  5.4* 22 1999 Example 2038 C22 H25 Br F2 N4 O2 495  5.4* 23 2000 *Yield of TFA salt.

Example 2001 Preparation of 1-(3-Carbamoylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 924)

EDCI (10.7 mg), 1-hydroxybenzotriazole hydrate (7.5 mg), Et₃N (15.4 mg), 0.5 M NH₃ in dioxane (0.1 mL, 0.05 mmol) and DMF (0.5 mL) were added to a solution of 1-(3-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (19.4 mg, 0.041 mmol) in CHCl₃ (2.5 mL). The reaction mixture was stirred at 25° C. for 20 h, washed with 2 N aqueous NaOH (2×2 mL) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford 1-(3-carbamoylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 924) as a pale yellow solid (17.9 mg, 92%): The purity was determined by RPLC/MS (89%); ESI/MS m/e 447.3 (M⁺+H, C₂₄H₂₇F₃N₄O₃).

Example 2002 Preparation of 1-(4-Carbamoylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 925)

Compound No. 925 was synthesized pursuant to methods of Example 2001 using the corresponding reactant: 14.2 mg, 72%; The purity was determined by RPLC/MS (86%); ESI/MS m/e 447 (M⁺+H, C₂₄H₂₇F₃N₄O₃).

Example 2003 Preparation of 1-(4-Aminobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 516)

A solution of 1-(4-nitrobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (22.4 mg, 0.047 mmol) in EtOH (3 mL) was hydrogenated at 1 atm for 1 h in the presence of 5% palladium on charcoal (10 mg) at 25° C. The catalyst was removed by filtration and washed with EtOH (5 mL). The combined filtrate was evaporated to afford 1-(4 aminobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 516) as a pale yellow solid (20.1 mg, 96%). The purity was determined by RPLC/MS (99%); ESI/MS m/e 449.1 (M⁺+H, C₂₃H₂₇F₃N₄O₂).

Examples 2004 and 2005

Compounds No. 517 and 518 were synthesized pursuant to methods of Example 2003 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 49.

TABLE 49 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 2004 517 C23 H27 F3 N4 O2 449 26.5 78 Example 2005 518 C23 H27 F3 N4 O2 449 25.3 71

Example 2006 Preparation of 1-{4-(Benzoylamino)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 519)

EDCI (4.7 mg), 1-hydroxybenzotriazole hydrate (3.3 mg), Et₃N (2.5 mg) and benzoic acid (3.0 mg) were added to a solution of 1-(4-aminobenzyl)-4[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (10.1 mg, 0.023 mmol) in CH₂Cl₂ (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2×2 mL) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford a yellow oil which was. purified by preparative TLC (SiO₂, 10% CH₃OH—CH₂Cl₂) to give 1-{4-(benzoylamino)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 519) as a colorless oil (4.6 mg, 36%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 553.2 (M⁺+H, C₃₀H₃₁F₃N₄O₃).

Example 2007 Preparation of 1-{4-(Piperidinocarbonyl)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1572)

Piperidine (0.04 mmol), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL), 1-hydroxybenzotriazole hydrate (0.45 mmol) in DMF (0.15 mL) were added to a solution of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (0.040 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 17 h, loaded onto Varian™ SCX column, and washed with CHCl₃/CH₃OH 1:1 (5 mL) and CH₃OH (5 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 1{-4-(piperidinocarbonyl)benzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1572) (14.3 mg, 66%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 545 (M⁺+H, C₂₉H₃₅F₃N₄O₃).

Examples 2008-2015

The compounds of this invention were synthesized pursuant to methods of Example 2007 using the corresponding reactant respectively. The ESI/MS data and yields are summarized in Table 50.

TABLE 50 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 2008 1573 C31 H33 F3 N4 O4 583 17.6 76 Example 2009 1574 C31 H33 F3 N4 O3 567 18.8 83 Example 2010 1575 C30 H30 Cl F3 N4 O3 587 3.2 14 Example 2011 1576 C28 H33 F3 N4 O4 547 21.1 97 Example 2012 1577 C26 H31 F3 N4 O4 521 5.1 24 Example 2013 1578 C31 H33 F3 N4 O3 567 16.9 75 Example 2014 1579 C31 H33 F3 N4 O3 567 6.0 26 Example 2015 1580 C29 H35 F3 N4 O3 545 15.1 69

Example 2016 Preparation of 1-[4-(Chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine

A mixture of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (240 mg) and thionyl chloride (1 mL) was stirred at room temperature for 12 h and the excess thionyl chloride was removed under reduced pressure to give desired 1-[4-(chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl{aminomethyl]piperidine. The acid chloride was used without further purification.

Example 2017 Preparation of 1-[4-{N-(2-Methoxyethyl)carbamoyl}benzyl]-4-[}N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1612)

A mixture of 1-[4-(chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (0.042 mmol), 2 methoxyethylamine (3.8 mg, 0.050 mmol), piperidinomethylpolystyrene (46 mg) and dichloromethane (1.5 mL) was stirred at room temperature for 17 h. Water (0.020 mL) was added and the mixture was stirred for 30 min. Methanol (1 mL) was added and the mixture was loaded onto Varian™ SCX column, and washed with CH₃OH (10 mL). Product was eluted off using 2 N NH₃ in CH₃OH (5 mL) and concentrated to afford 1-[4-{N-(2-methoxyethyl)carbamoyl}benzyl]-4-[(N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1612) (26.7 mg, 100%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 535.2 (M⁺+H, C₂₇H₃₃F₃N₄O₄).

Examples 2018-21020

The compounds of this invention were synthesized pursuant to methods of Example 2017 using the corresponding reactant respectively. Preparative TLC, if needed, afforded the desired material. The ESI/MS data and yields are summarized in Table 51.

TABLE 51 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 1610 C31 H30 F6 N4 O3 621.2 4.4 14 2018 Example 1611 C30 H29 Cl2 F3 N4 O3 621.2 35.7 quant 2019 Example 1613 C32 H35 F3 N4 O3 581.2 29.9 quant 2020

Example 2021 Preparation of 4-[N-{5-Bromo-2-(methylamino)benzoyl}glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1427)

A solution of 4-{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1042) (50 mg, 0.10 mmol) in triethyl orthoformate (6.5 mL) was stirred at 150° C. for 17 h. Concentration afforded a yellow solid. To a solution of the yellow solid in ethanol (3 mL) was added sodium borohydride (7.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 14 h. A resulting white precipitate was resolved in dichloromethane and the solution was washed with 1 N aqueous NaOH (2 mL). The organic layer was separated, dried over K₂CO₃, filtered and evaporated. Column chromatography (SiO_(2, 20)% MeOH/CHCl₃) gave 4-[N-{5-bromo-2-(methylamino)benzoyl}glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1427) (40 mg, 80): The purity was determined by RPLC/MS (100%); ESI/MS m/e 505 (C₂₃H₂₈BrClF₆N₄O₂).

Example 2022 Preparation of 4-[N-{5-Bromo-2-(dimethylamino)benzoyl}glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1428)

Sodium cyanoborohydride (26 mg, 0.42 mmol) and acetic acid (14 μL) was added successively to a mixture of 4-{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1042) (67 mg, 0.14 mmol), 37% formaldehyde solution in water (0.112 mL, 1.4 mmol), acetonitrile (2 mL), and methanol (1.5 mL). After the solution was stirred at 50° C. for 30 h, 1 N aqueous NaOH and dichloromethane were added. The aqueous layer was separated and the organic layer was dried over K₂CO₃, filtered and evaporated. Column chromatography (SiO_(2, 20)% MeOH/AcOEt) gave 4-[N-{5-bromo-2-(dimethylamino)benzoyl}glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1428) (60 mg, 82%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 523 (C₂₄H₃₀BrClF₆N₄O₂).

Example 2323 Preparation of 4-[{N-(5-Bromo-2-(methylsulfonylamino)benzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1581)

A mixture of 4-[{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (25 mg, 0.05 mmol), methanesulfonyl chloride (0.0045 mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 h. The reaction mixture was purified with column chromatography (SiO₂), loaded onto Varian™ SAX column, and washed with CH₃OH (5 mL). Product was eluted off using 0.1 N HCl in CH₃OH (5 mL) and concentrated to afford 4-[{N-(5-bromo-2-(methylsulfonylamino)benzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1581) (5.4 mg, 19%): ESI/MS m/e 573.0 (M⁺+H, C₂₃H₂₈BrClN₄O₄S).

Example 2024 Preparation of 4-[{N-(5-Bromo-2-(bis(methylsulfonyl)amino)benzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1582)

A mixture of 1-(4-chlorobenzyl)-4-[{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl]piperidine (57 mg, 0.10 mmol), methanesulfonyl chloride (0.018 mL, 0.24 mmol), triethylamine (0.068 mL) and dichloromethane (2 mL) was stirred at room temperature for 8 h. Aqueous 1 N NaOH solution (1 mL) was added and the mixture was extracted with dichloromethane (2 mL×3). The combined extracts were dried over K2 C03, filtered and evaporated. Column chromatography (SiO₂) gave 4-[{N-(5-bromo-2-(bis(methylsulfonyl)amino)benzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1582) (40 mg, 62%): ESI/MS m/e 651 (M⁺+H, C₂₄H₃₀BrClN₄O₆S₂).

Example 2025 Preparation of 1-(4-Chlorobenzyl)-1-methyl-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidinium iodide (Methylammonium iodide of Compound No. 461)

A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (30 mg, 0.087 mmol) in CH₃CN (1.0 mL) and (piperidinomethyl)polystyrene (80 mg, 2.7 mmol base/g resin) were added to a solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol) in CH₃CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2 h. Phenyl isocyanate (10.4 mg, 0.087 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH₃OH (20 mL). Product was eluted off using 2 N NH₃ in CH₃OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a colorless oil used without purification. Iodomethane (28 mg, 0.20 mmol) was added to a solution of 1-(4-chlorobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine in CH₃CN (2.0 mL) and the reaction mixture was stirred at 70° C. for 4 h. The solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-1-methyl-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidinium iodide as a pale yellow oil (31.7 mg, 71%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 482.1 (M⁺, C₂₄H₂₈ClF₃N₃O₂).

Example 2026 Preparation of 1-{4-Chlorobenzyl}-4-[N-methyl-N-{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 520)

Formaldehyde (108 mg, 1.33 mmol, 37% wt solution in H₂O) was added to a solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (318 mg, 1.33 mmol) and NaBH₃CN (668 mg) in 10% CH₃COOH/CH₃OH (3 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded on DOWEX™ 50W×2 column (10 mL) and washed with CH₃OH (100 mL). Product was eluted off using 2 N NH₃ in CH₃OH (100 mL) and concentrated to afford 173 mg of crude 1-(4-chlorobenzyl)-4-{(methylamino)methyl}piperidine as a colorless oil used without purification.

EDCI (85 mg), 1-hydroxybenzotriazole hydrate (60 mg) were added to a solution of 1-(4-chlorobenzyl)-4-{(methylamino)methyl}piperidine (111 mg, 0.44 mmol) in CH₂Cl₂ (4 mL). The reaction mixture was stirred at 25° C. for 1 h and then washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford an yellow oil which was purified by preparative TLC (SiO₂, 5% CH₃OH/CH₂Cl₂) to give 1-(4-chlorobenzyl)-4-[N-methyl-N-{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 520) as a pale yellow oil (14.0 mg, 3.4%). The purity was determined by RPLC/MS (99%); ESI/MS m/e 482.1 (M⁺+H, C₂₄H₂₇ClF₃N₃O₂).

Reference Example 37 Preparation of 3-Aminohomopiperidine

A solution of DL-α-amino-ε-caprolactam (2 g, 16 mmol) in THF (70 mL) was treated with 1 M BH₃-THE solution (80 mL) and heated to reflux for 3 h. 2 N aqueous HCl solution (50 mL) was added and the reaction was heated to reflux for an additional hour before cooling to 25° C. The reaction was basicified (pH 10) by the addition of 4 N NaOH solution and extracted with EtOAc (3×200 mL). The combined organic phases were washed with saturated aqueous NaHCO₃, dried (MgSO₄) and concentrated to yield the desired material (990 mg, 54%) which was used without any further purification.

Reference Example 38 Preparation of 3-Amino-1-(4-chlorobenzyl)homopiperidine

A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH₃CN (45 mL) was treated with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K₂CO₃ (828 g, 6 mmol) and heated to 70° C. for 9 h. The reaction mixture was cooled to 25° C. and concentrated to afford a yellow solid. The residue was partitioned between H₂O (5 mL) and EtOAc (50 mL), and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na₂SO₄) and concentrated. The resulting yellow oil was purified by chromatography (SiO₂, 5-20% CH₃OH—CH₂Cl₂ gradient elution) to afford the desired product as a yellow oil (639 mg, 93%).

Example 2027 Preparation of 1-(4-Chlorobenzyl)-3-{(4-benzoylbutyryl)amino}homopiperidine (Compound No. 994)

A solution of 3-amino-1-(4-chlorobenzyl)homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equiv.) in CHCl3 (1 mL) was treated with EDCI (23 mg), HOBt (16.2 mg) and Et₃N (15.2 μL), and stirred at 25° C. for 16 h. The reaction mixture was diluted with CH₂Cl₂ (0.5 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL), dried by filtration through a PTFE membrane and concentrated to afford 1-(4-chlorobenzyl)-3-{(4-benzoylbutyryl)amino}homopiperidine (compound No. 994) (43 mg, 99%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 413 (M⁺+H, C₂₄H₂₉ClN₂O₂)

Examples 2028-2042

The compounds of this invention were synthesized pursuant to methods of Example 2027 using the corresponding reactant respectively. Chromatography (HPLC-C18), if needed, afforded the desired material as the TPA salt. The ESI/MS data and yields are summarized in Table 52.

TABLE 52 Com- pound ESI/MS Yield Yield No. Molecular Formula m/e (mg) (%) Example 2028 943 C23 H25 Cl F3 N3 O2 468  6 28 Example 2029 944 C23 H28 Cl N3 O2 414  5 29 Example 2030 945 C22 H25 Cl N4 O4 445  6 30 Example 2031 946 C23 H27 Cl N4 O4 459  5 24 Example 2032 947 C25 H31 Cl N2 O4 459  4 20 Example 2033 948 C24 H29 Cl2 N3 O2 462  6 32 Example 2034 949 C25 H32 Cl N3 O2 442  6 31 Example 2035 988 C23 H25 Cl F3 N3 O2 468 45 92 Example 2036 989 C23 H28 Cl N3 O3 430 44 97 Example 2037 990 C22 H26 Cl N3 O2 400 41 99 Example 2038 991 C23 H27 Cl N2 O2 399 41 97 Example 2039 992 C25 H31 Cl N2 O4 459 47 98 Example 2040 993 C25 H31 Cl N2 O2 427 44 98 Example 2041 995 C25 H31 Cl N2 O3 443 44 95 Example 2042 996 C24 H31 Cl N4 O2 443  5* 11 *Yield of TFA salt.

Example 2043 Measurement of Inhibition of MIP-1α Binding to THP-1 Cells by Test Compounds

Human monocytic leukemia cell line THP-1 was suspended in assay buffer (RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 1×10⁷ cells/mL. The test compound was diluted in the assay buffer and used as the test compound solution. Iodinated human MIP-1α (DuPont NEN Co.) was diluted in assay buffer to 250 nCi/mL and used as the labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 μL), and incubated for one hour at 18° C.

After the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (200 μL of cold PBS was added and then filtered). The filter was air-dried and 25 μL of liquid scintillator was added into each well. The radioactivity retained by the cells on the filter were measured using TopCounit (Packard Instrument Co.).

To calculate the ability of test compounds to inhibit binding of human MIP-1α to THP-1 cells, non-specific binding determined by adding 100 ng of unlabeled human MIP-1α (Peprotech Co.) in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.

Inhibition (%)={1−(A−B)/(C−B)}×100

(A, counts with test compound added; B, counts with 100 ng of unlabeled human MIP-1α added; C, counts with [¹²⁵I]-labeled human MIP-1α added).

When inhibition by the cyclic amine derivative of this invention was measured, for example, the following compounds demonstrated 20-50%, 50%-80% and >80% inhibitory activity at 2 μM or 10 μM, respectively. These compounds 20%-50% inhibition at 10 μM: compound Nos. 29, 37, 41, 45, 46, 47, 50, 82, 85, 107, 120, 134, 214, 217, 218, 220, 222, 225, 226, 227, 228, 229, 230, 231, 233, 234, 236, 237, 238, 333, 334, 335, 336, 338, 340, 342, 347, 348, 349, 350, 352, 357, 359, 361, 366, 372, 374, 375, 376, 380, 382, 383, 385, 470, 471, 472, 473, 474, 483, 484, 488, 489, 491, 497, 499, 500, 502, 506, 508, 510, 514, 515, 518, 524, 543, 553, 554, 555, 556, 563, 571, 575, 576, 578, 579, 580, 583, 586, 587, 588, 590, 591, 592, 595, 596, 598, 603, 610, 611, 612, 614, 624, 625, 626, 629, 635, 638, 639, 640, 641, 642, 643, 644, 646, 647, 648, 649, 652, 653, 658, 659, 660, 665, 666, 669, 671, 675, 677, 679, 681, 682, 684, 691, 695, 696, 700, 702, 704, 706, 711, 712, 714, 717, 721, 723, 724, 726, 727, 728, 729, 731, 737, 739, 740, 741, 742, 744, 746, 765, 767, 772, 773, 774, 775, 776, 780, 781, 785, 786, 787, 788, 790, 791, 792, 793, 795, 796, 797, 798, 805, 806, 807, 810, 813, 820, 821, 822, 824, 825, 827, 829, 830, 833, 834, 837, 838, 844, 853, 855, 873, 877, 878, 880, 882, 887, 888, 891, 894, 901, 903, 904, 905, 911, 929, 932, 933, 935, 938, 940, 948, 993, 9516, 1006, 1018, 1026, 1028, 1035, 1048, 1053, 1054, 1055, 1056, 1068, 1070, 1071, 1072, 1073, 1075, 1076, 1081, 1763, 1764.

50%-80% inhibition at 10 μM: Compound Nos. 1, 2, 3, 4, 7, 13, 22, 23, 24, 25, 27, 31, 32, 38, 48, 83, 119, 121, 123, 131, 215, 216, 221, 235, 337, 351, 354, 358, 362, 363, 365, 367, 368, 369, 373, 378, 381, 384, 458, 459, 463, 465, 466, 467, 468, 478, 479, 480, 482, 485, 486, 487, 492, 493, 494, 495, 496, 498, 501, 503, 504, 507, 511, 512, 513, 520, 523, 527, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 510, 541, 542, 545, 546, 547, 548, 549, 550, 551, 552, 558, 559, 560, 561, 562, 565, 567, 568, 569, 570, 572, 573, 574, 577, 581, 582, 594, 597, 599, 600, 602, 604, 606, 607, 608, 609, 613, 615, 616, 618, 619, 620, 621, 628, 630, 631, 632, 633, 634, 636, 637, 645, 651, 654, 655, 657, 661, 662, 664, 673, 674, 676, 678, 680, 683, 685, 687, 688, 689, 693, 703, 705, 707, 708, 709, 710, 713, 716, 718, 719, 720, 725, 730, 732, 733, 734, 735, 736, 749, 750, 751, 752, 753, 754, 756, 758, 760, 762, 763, 764, 766, 768, 769, 770, 771, 777, 778, 779, 784, 794, 799, 800, 802, 804, 808, 809, 811, 812, 815, 816, 819, 828, 831, 832, 835, 836, 839, 640, 845, 846, 847, 848, 850, 851, 854, 857, 868, 859, 860, 861, 862, 863, 865, 866, 867, 868, 872, 874, 876, 886, 899, 910, 942, 998, 1004, 1005, 1007, 1013, 1015, 1016, 1017, 1019, 1020, 1021, 1022, 1024, 1030, 1037, 1042, 1043, 1044, 1045, 1046, 1047, 1049, 1050, 1052, 1059, 1060, 1061, 1067, 1069, 1074, 1078, 1079, 1080, 1766.

>80% inhibition at 10 μM: Compound Nos. 461, 464, 469, 481, 490, 505, 509, 521, 526, 528, 544, 564, 566, 601, 605, 617, 622, 623, 627, 650, 656, 663, 668, 672, 686, 690, 692, 694, 715, 743, 747, 748, 755, 757, 759, 761, 782, 783, 803, 814, 817, 818, 826, 849, 856, 864, 869, 670, 871, 999, 1000, 1001, 1002, 1003, 1008, 1009, 1010, 1011, 1012, 1023, 1029, 1031, 1032, 1033, 1034, 1036, 1038, 1039, 1040, 1041, 1051, 1057, 1058, 1062, 1063, 1064, 1065, 1066, 1082, 1083.

20%-50% inhibition at 2 μM: Compound Nos. 1042, 1043, 1244, 1245, 1416, 1435, 1436, 1438, 1441, 1480, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1601, 1660, 1672, 1687, 1724, 1779, 1780, 1787, 1795, 1796, 1798, 1799, 1802, 1893, 1894, 1898, 1900, 1915, 1919, 1920, 2092, 2096, 2098, 2100. 50%-80% inhibition at 2 μM: Compound Nos. 1190, 1414, 1600, 2091, 2094, 2095. >80% inhibition at 2 μM: Compound Nos. 2093, 2097, 2099, 2103, 2104.

Example 2044 Measurement of Inhibition of MCP-1 Binding to THP-1 Cells

1. Construction of recombinant baculovirus carrying the human MCP-1 gene

Based on the previously published human MCP-1 gene sequence (for example T. Yoshirnura et al., FEBS Lett., 1989, 244, 487-493), two synthetic DNA primers (5′-CACTCTAGACTCCAGCATGA-3′ and 5′-TAGCTGCAGATTCTTGGGTTG-3′) flanked by restriction enzyme sites were used to amplify a DNA fragment from cDNA derived from human endothelial cells (purchased from Kurabow Co.); the amplified fragment was cut with the restriction enzymes (PstI and XbaI), ligated into a transfer vector pVL1393 (Invitrogen Co.), and the resulting vector was co-transfected along with infectious baculovirus into Sf-9 insect cells and the supernatant was plaque assayed to yield human MCP-1 gene baculovirus recombinant.

2. Synthesis of [¹²⁵I]-labeled human MCP-1 expressed in baculovirus

Using the method of K. Ishii et al. (Biochem Biophys Research Communications, 1995, 206, 955-961), 5×10⁶ Sf-6 insect cells was infected with 5×10⁷ PFU (plaque forming units) of the above human MCP-1 recombinant baculovirus and cultured for 7 days in Ex-Cell 401 medium. The culture supernatant was affinity purified using a heparin Sepharose column (Pharmacia Co.) and then further purified using reverse phase HPLC (Vydac C18 column) to prepare purified human MCP-1. The purified human MCP-1 was protein labeled by Amersham Co. using the Bolton Hunter method to yield [¹²⁵I]-labeled baculovirus expressed human MCP-1 (specific activity 2000 Ci/mmol).

3-1. Measurement of inhibition of binding of [¹²⁵I]-labeled baculovirus expressed human MCP-1 to THP-1 cells (Method 1)

Human monocytic leukemia cell line THP-1 was suspended in assay buffer (RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 1×10⁷ cells/mL. The test. compound was diluted in the assay buffer and used as the test compound solution. [¹²⁵I]-labeled human MCP-1 described above was diluted in assay buffer to 1 mCi/mL and used as the labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 μL), and incubated for one hour at 18° C.

After the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (200 μL of cold PBS was added and then filtered). The filter was air-dried and 25 μL of liquid sciatillator was added into each well. The radioactivity retained by the cells on the filter were measured using TopCount (Packard Instrument Co.).

To calculate the ability of test compound to inhibit binding of human MCP-1 to THP-1 cells, non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.

Inhibition (%)=(1−(A−B)/(C−B))×100

(A, counts with test compound added; B, counts with 100 ng of unlabeled human MCP-1 added; C, counts with [¹²⁵I]-labeled human MCP-1 added).

When inhibition by the cyclic amine derivative of this invention was measured, for example, the following compounds demonstrated 20%-50%, 50%-80 % and >80% inhibitory activity at 1 μM, 10 μM or 100 μM, respectively. These compounds are

20%-50% inhibition at 100 μM: Compound Nos. 3, 6, 11, 15, 16, 19, 28, 44, 88, 92, 94, 104, 111, 112, 124, 125, 133, 219, 220, 224, 228, 236, 338, 343, 346, 347, 348, 349, 362, 363, 367, 368, 371, 373, 381, 618, 847, 849, 850, 866, 867, 869, 870, 871, 872, 873. 50%-80% inhibition at 100 μM: Compound Nos. 1, 8, 10, 12, 18, 21, 26, 30, 33, 35 35, 39, 84, 89, 90, 91, 96, 97, 98, 99, 100, 101, 103, 106, 108, 109, 110, 116, 122, 126, 216, 218, 221, 225, 226, 231, 330, 332, 333, 334, 337, 341, 342, 350, 352, 354, 356, 359, 360, 361, 364, 366, 374, 375, 379, 382, 462, 463, 464, 557, 686, 840, 841, 842, 843, 844, 845, 846, 848, 862, 863, 864, 865, 868.

>80% inhibition at 100 μM: Compound Nos. 2, 4, 5, 7, 13, 14, 17, 20, 22, 23, 24, 25, 27, 29, 31, 32, 34, 36, 38, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 83, 85, 86, 95, 102, 105, 107, 113, 114, 115, 119, 120, 121, 123, 127, 128, 129, 130, 131, 132, 134, 214, 215, 217, 227, 237, 238, 331, 335, 336, 339, 340, 345, 351, 355, 357, 358, 383, 458, 459, 460, 466, 558, 851, 852, 861, 874. 20%-50% inhibition at 10 μM: Compound Nos. 12, 18, 30, 34, 40, 42, 43, 51, 52, 53, 54, 55, 56, 57, 59, 60, 64, 66, 75, 76, 77, 78, 79, 82, 89, 90, 97, 98, 102, 103, 116, 127, 128, 129, 130, 132, 135, 136, 140, 141, 144, 156, 157, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 178, 179, 190, 191, 192, 195, 197, 200, 202, 203, 204, 205, 208, 233, 234, 235, 239, 240, 241, 242, 243, 245, 247, 249, 250, 255, 263, 264, 269, 274, 278, 279, 282, 306, 316, 317, 323, 324, 380, 404, 409, 433, 446, 448, 449, 451, 470, 471, 473, 476, 479, 486, 488, 489, 497, 498, 499, 501, 504, 507, 508, 509, 510, 512, 514, 516, 519, 527, 530, 532, 542, 545, 560, 563, 564, 565, 566, 568, 569, 572, 573, 574, 575, 578, 583, 584, 586, 587, 589, 590, 599, 600, 601, 603, 606, 612, 613, 620, 621, 622, 624, 625, 627, 629, 630, 632, 634, 636, 637, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 658, 678, 682, 687, 692, 694, 764, 775, 856, 857, 860, 881, 882, 883, 884, 890, 892, 899, 900, 903, 905, 907, 908, 911, 912, 916, 917, 921, 922, 923, 925, 927, 931, 932, 935, 939, 940, 968, 986, 1039, 1041, 1045, 1047, 1062, 1063, 1083. 50%-80% inhibition at 10 μM: Compound Nos. 7, 32, 36, 61, 62, 63, 65, 67, 69, 70, 71, 72, 73, 74, 81, 91, 105, 114, 121, 123, 134, 137, 138, 139, 146, 147, 148, 149, 151, 154, 165, 177, 232, 244, 248, 251, 252, 253, 256, 259, 261, 266, 267, 276, 286, 292, 293, 295, 301, 305, 307, 310, 314, 315, 320, 322, 328, 434, 435, 436, 437, 439, 440, 443, 447, 450, 452, 453, 454, 455, 456, 468, 469, 472, 474, 475, 477, 478, 480, 481, 482, 483, 485, 490, 493, 494, 500, 505, 511, 517, 520, 529, 534, 540, 543, 544, 548, 555, 556, 561, 562, 570, 576, 579, 611, 617, 853, 854, 855, 858, 859, 875, 877, 879, 880, 885, 886, 887, 888, 891, 894, 895, 904, 906, 909, 910, 913, 914, 918, 928, 930, 933, 937, 938, 945, 970, 1040, 1044, 1046. >80% inhibition at 10 μM: Compound Nos. 31, 45, 46, 48, 58, 68, 80, 83, 113, 115, 142, 143, 145, 150, 152, 265, 268, 272, 275, 283, 285, 287, 288, 290, 291, 294, 296, 297, 302, 308, 309, 313, 321, 325, 326, 358, 438, 441, 442, 444, 445, 457, 466, 467, 484, 487, 491, 492, 495, 496, 503, 518, 537, 538, 547, 554, 876, 878, 919, 929, 943. 20%-50% inhibition at 1 μM: Compound Nos. 1118, 1121, 1136, 1143, 1146, 1158, 1159, 1167, 1170, 1359, 1361, 1362, 1363. 50%-80% inhibition at 1 μM: Compound Nos. 1133, 1134, 1137, 1141, 1156, 1161, 1162, 1163, 1164, 1166. >80% inhibition at 1 μM: Compound No. 1147.

3-2. Measurement of inhibition of binding of [¹²⁵I]-labeled baculovirus expressed human MCP-1 to THP-1 cells (Method 2)

Human monocytic leukemia cell line THP-1 was suspended in assay buffer (50 mM HEPES, pH 7.4, 1.0 mM CaCl₂, 5.0% mM MgCl₂, 0.5% BSA) to give a cell suspension of a concentration of 1×10⁷ cells/mL. The test compound was diluted in the assay buffer and used as the test compound solution. [¹²⁵I]-labeled human MCP-1 described above was diluted in assay buffer to 1 mCi/mL and used as the labeled ligand solution. In a 96 well filter plate (Millipore Co.), 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 μL), and incubated for one hour at 18° C.

After the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (200 μL of cold PBS was added and then filtered). The filter was air-dried and 25 μL of liquid scintillator was added into each well. The radioactivity retained by the cells on the filter were measured using TopCount (Packard Instrument Co.).

To calculate the ability of test compound to inhibit binding of human MCP-1 to THP-1 cells, non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.

Inhibition (%)={1−(A−B)/(C−B)}×100

(A, counts with test compound added; B, counts with 100 ng of unlabeled human MCP-1 added; C, counts with [¹²⁵I]-labeled human MCP-1 added).

When inhibition by the cyclic amine derivative of this invention was measured, for example, the following compounds demonstrated 20%-50%, 50%-80% and >80% inhibitory activity at 0.2 μM, 1 μM or 10 μM, respectively. These compounds are 20%-50% inhibition at 10 μM: Compound No. 1560. 50%-80% inhibition at 10 μM: Compound No. 1550. >80% inhibition at 10 μM: Compound Nos. 541, 1042, 1043, 1559. 20%-50% inhibition at 1 μM: Compound Nos. 1098, 1100, 1101, 1104, 1105, 1109, 1110, 1116, 1174, 1175, 1176, 1178, 1187, 1188, 1189, 1197, 1198, 1199, 1200, 1201, 1202, 1209, 1210, 1211, 1212, 1222, 1225, 1229, 1230, 1237, 1238, 1243, 1250, 1259, 1261, 1265, 1266, 1272, 1277, 1282, 1294, 1299, 1302, 1307, 1315, 1318, 1319, 1320, 1329, 1330, 1335, 1336, 1337, 1343, 1344, 1353, 1355, 1356, 1357, 1358, 1368, 1372, 1385, 1386, 1392, 1400, 1413, 1422, 1423, 1425, 1426, 1429, 1430, 1432, 1437, 1440, 1445, 1446, 1447, 1448, 1450, 1452, 1453, 1455, 1458, 1459, 1461, 1463, 1464, 1466, 1468, 1469, 1470, 1471, 1474, 1479, 1482, 1485, 1507, 1508, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1518, 1519, 1521, 1522, 1524, 1535, 1538, 1540, 1542, 1544, 1571, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1585, 1587, 1598, 1602, 1603, 1604, 1609, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1622, 1627, 1630, 1643, 1646, 1662, 1669, 1716, 1717, 1723, 1728, 1731, 1733, 1736, 1739, 1740, 1747, 1750, 1755, 1757, 1758, 1759, 1760, 1761, 1762, 1769, 1770, 1771, 1772, 1773, 1774, 1777, 1783, 1784, 1785, 1791, 1793, 1904, 1911, 1917, 2057, 2061, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2071, 2072, 2073, 2074, 2075, 2076, 2080, 2081, 2082, 2110, 2112, 2123, 2130, 2131, 2139. 50%-80% inhibition at 1 μM: Compound Nos. 37, 298, 318, 1084, 1091, 1103, 1106, 1108, 1111, 1113, 1114, 1115, 1138, 1142, 1165, 1179, 1190, 1192, 1193, 1195, 1196, 1204, 1205, 1206, 1207, 1208, 1245, 1246, 1255, 1257, 1256, 1262, 1263, 1293, 1300, 1342, 1351, 1352, 1354, 1370, 1371, 1373, 1375, 1377, 1378, 1380, 1381, 1383, 1384, 1391, 1411, 1412, 1414, 1417, 1418, 1419, 1421, 1424, 1431, 1436, 1439, 1449, 1454, 1456, 1457, 1460, 1462, 1472, 1473, 1487, 1502, 1504, 1506, 1517, 1525, 1526, 1527, 1529, 1530, 1531, 1532, 1533, 1534, 1536, 1537, 1539, 1541, 1545, 1593, 1600, 1601, 1606, 1608, 1619, 1620, 1621, 1623, 1624, 1625, 1626, 1628, 1629, 1645, 1650, 1654, 1658, 1663, 1664, 1665, 1670, 1671, 1672, 1673, 1675, 1678, 1679, 1681, 1684, 1687, 1688, 1689, 1690, 1711, 1712, 1714, 1718, 1722, 1725, 1726, 1727, 1729, 1730, 1732, 1734, 1735, 1737, 1741, 1742, 1743, 1744, 1745, 1746, 1748, 1751, 1753, 1754, 1756, 1779, 1781, 1782, 1786, 1788, 1789, 1790, 1792, 1795, 1797, 1798, 1800, 1801, 1804, 1848, 1862, 1883, 1885, 1886, 1887, 1889, 1893, 1894, 1903, 1905, 1910, 1912, 1913, 1914, 1918, 1922, 1976, 1985, 2027, 2035, 2062, 2083, 2084, 2088, 2089, 2090, 2111, 2124, 2125, 2126, 2135. >80% inhibition at 1 μM: Compound Nos. 299, 311, 312, 329, 1042, 1043, 1085, 1119, 1191, 1203, 1220, 1228, 1236, 1244, 1256, 1288, 1295, 1308, 1310, 1376, 1382, 1393, 1395, 1415, 1416, 1420, 1435, 1438, 1441, 1480, 1481, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1607, 1634, 1660, 1661, 1666, 1668, 1695, 1696, 1697, 1698, 1699, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1713, 1724, 1749, 1752, 1775, 1776, 1778, 1780, 1787, 1794, 1796, 1799, 1802, 1803, 1841, 1869, 1870, 1871, 1872, 1876, 1877, 1892, 1896, 1897, 1898, 1899, 1900, 1901, 1902, 1906, 1907, 1906, 1909, 1915, 1916, 1919, 1920, 1921, 2085, 2086, 2087, 2113, 2114, 2118, 2119, 2120, 2121, 2122, 2127, 2128, 2129, 2132, 2133, 2136, 2137, 2138, 2159, 2161, 2162, 2187, 2189, 2193. 20%-50% inhibition at 0.2 μM: Compound Nos. 1680, 1682, 1686, 1691, 1694, 1700, 1805, 1810, 1811, 1812, 1813, 1815, 1816, 1817, 1818, 1819, 1820, 1824, 1825, 1826, 1827, 1828, 1832, 1833, 1834, 1835, 1836, 1839, 1840, 1842, 1843, 1851, 1852, 1853, 1854, 1955, 1856, 1859, 1859, 1860, 1863, 1864, 1865, 1866, 1868, 1874, 1878, 1879, 1880, 1889, 1890, 1691, 1895, 1926, 1927, 1928, 1929, 1930, 1934, 1935, 1937, 1945, 1946, 1951, 1952, 1953, 1954, 1959, 1960, 1961, 1962, 1966, 1969, 1970, 1971, 1972, 1973, 1977, 1978, 1979, 1980, 1981, 1985, 2014, 2027, 2028, 2033, 2035, 2039, 2040, 2041, 2042, 2044, 2045, 2046. 50%-80% inhibition at 0.2 μM: Compound Nos. 1677, 1678, 1679, 1681, 1687, 1698, 1689, 1690, 1695, 1697, 1808, 1809, 1841, 1848, 1861, 1862, 1869, 1870, 1871, 1872, 1873, 1876, 1877, 1883, 1884, 1885, 1886, 1887, 1889, 1893, 1894, 1976. >80% inhibition at 0.2 μM: Compound No. 1696, 1892.

Example 2045 Measurement of Inhibition of Binding of [¹²⁵I]-Labeled Human MCP-1 to Cells Expressing the MCP-1 Receptor.

1. Derivation of cells expressing the MCP-1 receptor

cDNA fragment containing the MCP-1 receptor reported by S. Yamagami et al., Biochemical Biophysical Research Communications 1994, 202, 1156-1162) was cloned into the expression plasmid pCEP4 (Invitrogen Co.) at the NotI site, and the plasmid obtained was transfected into the human kidney epithelial cell line 293-EBNA using the Lipofectamine reagent (Gibco-BRL Co.). The cells were cultured in the presence of the selective agent (Hygromycin), and a stably expressing transfectant line was obtained. The expression of the receptor was confirmed by binding of [¹²⁵I]-labeled human MCP-1.

2. Measurement of inhibition of binding of [¹²⁵I]-labeled baculovirus expressed human MCP-1 to the MCP-1 receptor expressing cells

The MCP-1 receptor expressing cells on tissue culture dishes were scraped using a cell scraper and suspended in assay buffer (D-MEM(Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 6×10⁶ cells/mL. The test compound was diluted in the assay buffer. The remainder of the procedure was as described in Example 2044.

When the inhibition by some typical compounds of the present invention was measured, the inhibitory activities were substantially the same as those in Example 2044, respectively.

Example 2046 Measurement of Inhibition of Cell Chemotaxis

In order to determine the inhibition of cell chemotaxis by the compounds of this invention, we measured cell chemotaxis caused by monocyte chemotactic factor MCP-1 using the human monocytic leukemia cell line THP-1 as the chemotactic cell according to the method of Fall et al. (J. Immunol. Methods, 190, 33,239-247). 2×10⁶ cells/mL of THP-1 cells (suspended in RPMI-1640 (Flow Laboratories Co.)+10% FCS) was placed in the upper chamber (200 μL) of a 96 well micro-chemotaxis chamber (Neuroprobe; registered tradename), and human recombinant MCP-1 in a same solution (Peprotech Co.) at a final concentration of 20 ng/mL was placed in the lower chamber, with a polycarbonate filter (PVP-free, Neuroprobe; registered tradename) placed between the two chambers. These were incubated at 37° C. for 2 hr in 5% CO₂.

The filter was removed, and the cells which had migrated to the underside of the filter was fixed, stained using Diff Quick (Kokusai Shiyaku Co.) and then quantitated using a plate reader (Molecular Device Co.) at a wavelength of 550 nm to determine the index of cell migration as a mean of 3 wells. In addition, test compounds were placed in the upper and lower chambers along with THP-1 and MCP-1, respectively, and the inhibition of cell migration (inhibition IC₅₀ (μM)) was determined. Inhibition was defined as {(cells migration induced MCP-1 with no test compound in the upper and lower chambers)—(cells migration with no MCP-1 added in the lower chamber)=100%}, and the concentration of the test compound which gave 50% inhibition was designated IC₅₀.

When inhibition by the cyclic amine derivative of this invention was measured, for example, the 50% inhibition concentration (IC₅₀) for the following compounds were IC₅₀, <0.1 μM. IC₅₀<0.1 μM: Compound Nos. 4, 37, 298, 299, 311, 312, 318, 329, 461, 886, 909, 1042, 1043, 1085, 1119, 1138, 1142, 1165, 1179, 1191, 1203, 1205, 1220, 1228, 1236, 1244, 1245, 1256, 1288, 1293, 1295, 1308, 1310, 1352, 1376, 1382, 1393, 1395, 1416, 1420, 1435, 1436, 1438, 1441, 1480, 1531, 1532, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1600, 1601, 1607, 1660, 1661, 1664, 1666, 1668, 1698, 1699, 1701, 1702, 1703, 1704, 1706, 1707, 1708, 1709, 1713, 1775, 1776, 1778, 1779, 1787, 1794, 1796, 1799, 1802, 1803, 1896, 1898, 1899, 1900, 1901, 1902, 1906, 1907, 1908, 1909, 191 S, 1916, 1919, 1920, 1921, 2087, 2114, 2128, 2129, 2132, 2137, 2141, 2144, 2157, 2158, 2189. 

What is claimed is:
 1. A compound of the formula (I) below:

a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt thereof, wherein R¹ is a phenyl group, a C₃-C₈ cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C₁-C₆ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₃-C₅ alkylene group, a C₂-C₄ alkylenoxy group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₄-C₉ N-cycloalkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a C₃-C₈ (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, a divalent group represented by the formula: —NH(C═O)O—, a divalent group represented by the formula: —NH(C═S)O—, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, atrifluoromethyl group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group; R² is a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C₁-C₆ alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl croup, or a C₁-C₆ alkoxy group, and when j=0, R² is not a hydroxy group; j represents an integer of 0-2; k represents an integer of 0-2; m represents an integer of 2-4, with the proviso that the total sum of k and m is 4; n represents 0 or 1; and further with the proviso that when k=2, m=2, n=0 and R¹ is an indolyl group, then j=0 and R² is a hydrogen atom; R³ is a hydrogen atom or a C₁-C₆ alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group; R⁴ and R⁵ are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C₁-C₆ alkyl group, in which the C₁-C₆ alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C₃-C₈ cycloalkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C₂-C₇ alkanoyl group, a C₂-C₇, alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, with the proviso that when one of R⁴ and R⁵ is a hydrogen atom, the other is not an isobutyl group, or R⁴ and R⁵ taken together form a 3 to 6 membered cyclic hydrocarbon; p represents 0 or 1; q represents 0 or 1; G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, —CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O—, or —O—CO—NH—, wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group, or R⁷ taken together with R⁵ represents C₂-C₅ alkylene group; R⁶ is a phenyl group, a C₃-C₈ cycloalkyl group, a C₃-C₈ cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₃-C₈ cycloalkyloxy group, a C₁C₆ alkylthio group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsufonyl group, a 3-phenylureido group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇, alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C₁-C₆ alkyl) sulfamoyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, a benzylamino group, a C₂-C₇ (alkoxycarbonyl)amino group, a C₁-C₆ (alkylsulfonyl)amino group, or a bis(C₁-C₆ alkylsulfonyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group with the proviso that when k=2, m=2, n=0, and R¹ is an unsubstituted phenyl group, then 1) C₁-C₆ alkyl group as a substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁶ is not substituted with amino group, and 2) R⁶ is not a benzyl group.
 2. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein k=1 and m=3 in the above formula (I).
 3. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein k=2 and m=2 in the above formula (I).
 4. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 3, wherein n=1 in the above formula (I).
 5. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein j=0 in the above formula(I).
 6. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein p=0, q=0 and G is a group represented by —NR⁷—CO— in the above formula (I).
 7. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein R² is a hydrogen atom, R³ is a hydrogen atom and R⁷ is a hydrogen atom in the above formula (I).
 8. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹ is one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₂-C₄ alkylenoxy group, a methylenedioxy group, a N-phenylcarbamoyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group in the above formula (I).
 9. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁶ is one or more of a halogen atom, a nitro group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a phenylsulfonyl group, a C₂-C₇ alkanoylamino group, or an amino group in the above formula (I).
 10. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein R¹ is a phenyl group or an isoxazolyl group in the above formula (I).
 11. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein R⁶ is a phenyl group, a furyl group, or a thienyl group in the above formula (I).
 12. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell using a pharmaceutical preparation containing a therapeutically effective amount of a compound represented by the formula (I) below:

a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C₁-C₆ alkyl addition salt thereof, wherein R¹ is a phenyl group, a C₃-C₈ cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy, group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C₁-C₆ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₃-C₅ alkylene group, a C₂-C₄ alkylenoxy group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇, alkanoylamino group, a C₂—C—, N-alkylcarbamoyl group, a C₄-C₉ N-cycloalkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a C₃-C₈ (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group; R² is a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C₁-C₆ alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group, and when j=0, R² is not a hydroxy group; j represents an integer of 0-2; k represents an integer of 0-2; m represents an integer of 2-4, with the proviso that the total sum of k and m is 4; n represents 0 or 1; R³ is a hydrogen atom or a C₁-C₆ alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, or a C₁-C₆ alkoxy group; R⁴ and R⁵ are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C₁-C₆ alkyl group, in which the C₁-C₆ alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C₃-C₈ cycloalkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a benzyloxy group a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C₂-C₇, alkanoyl group, a C₂-C-₇ alkoxycarbonyl group, a C₂-C₇ alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R⁴ and R⁵ taken together form a 3 to 6 membered cyclic hydrocarbon; p represents 0 or 1; q represents 0 or 1; G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, —CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O—, or —O—CO—NH—, wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group, or R⁷ taken together with R⁵ represents C₂-C₅ alkylene group; R⁶ is a phenyl groups, a C₃-C₈ cycloalkyl group, a C₃-C₈ cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C₃-C₈ cycloalkyl group, C₃-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₃-C₈ cycloalkyloxy group, a C₁-C₆ alkylthio group, a C₁-C₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsufonyl group, a 3-phenylureido group, a C₂-C₇ alkanoyl group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇, alkanoyloxy group, a C₂-C₇ alkanoylamino group, a C₂-C₇ N-alkylcarbamoyl group, a C₁-C₆ alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C₁-C₆ alkyl) sulfamoyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, a di(C₁-C₆ alkyl)amino group, a benzylamino group, a C₂-C₇ (alkoxycarbonyl)amino group, a C₁-C₆ (alkylsulfonyl)amino group, or a bis(C₁-C₆ alkylsulfonyl)amino group, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group.
 13. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein k=1 and m=3 in the above formula (I).
 14. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein k=2 and m=2 in the above formula (I).
 15. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 14, wherein n=1 in the above formula (I).
 16. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein j=0 in the above formula (I).
 17. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein p=0, q=0 and G is a group represented by —NR⁷—CO— in the above formula (I).
 18. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein R² is a hydrogen atom, R³ is a hydrogen atom and R⁷ is a hydrogen atom in the above formula (I).
 19. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, aromatic heterocyclic group, or condensed ring in R¹ is one or more of a halogen atom, a hydroxy group, a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group, a C₁-C₆ alkoxy group, a C₁-C₆ alkylthio group, a C₂-C₄ alkylenoxy group, a methylenedioxy group, a N-phenylcarbamoyl group, an amino group, a mono(C₁-C₆ alkyl)amino group, or a di(C₁-C₆ alkyl)amino group in the above formula (I).
 20. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein the substituent for the phenyl group, C₃-C₈ cycloalkyl group, C₃-C₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R⁶ is one or more of a halogen atom, a nitro group, a trifluoromethyl group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a phenylsulfonyl group, a C₂-C₇ alkanoylamino group, or an amino group in the above formula (I).
 21. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein R¹ is a phenyl group or an isoxazolyl group in the above formula (I).
 22. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein R⁶ is a phenyl group, a furyl group, or a thienyl group in the above formula (I).
 23. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein the chemokine is MIP-1α.
 24. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein the chemokine is MCP-1.
 25. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell as set forth in claim 12, wherein the chemokine receptor is CCR1.
 26. A method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on la target cell as set forth in claim 12, wherein the chemokine receptor is CCR2A or CCR2B.
 27. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine.
 28. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine.
 29. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine.
 30. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine.
 31. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-bromobenzyl)piperidine.
 32. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 1-(2-amino-4-chlorobenzyl)-4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine.
 33. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 1-(3-amino-4-methoxybenzyl)-4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine.
 34. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-{4-chloro-3-(methylamino)benzyl}piperidine.
 35. A compound, its pharmaceutically acceptable acid addition salt or its pharmaceutically acceptable C₁-C₆ alkyl addition salt as set forth in claim 1, wherein the compound is 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-thioxo-2,3-dihydro-1,3-benzoxazol-5-ylmethyl)piperidine. 